tag:blogger.com,1999:blog-50815378331143326202024-03-20T17:56:35.448-07:00High Tower PharmacologyDetailed examination of Stimulants, Supplements, and Anti-Aging Medicine.S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.comBlogger25125tag:blogger.com,1999:blog-5081537833114332620.post-55548851864689333722014-06-04T11:10:00.004-07:002014-06-04T11:11:54.579-07:00Alexander ShulginRest In Peace (17/6/1925 - 2/6/2014)<br />
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<img height="320" src="https://www.erowid.org/culture/characters/shulgin_alexander/images/shulgin_alexander9_med.jpg" width="235" /><br />
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<a href="http://www.independent.co.uk/news/people/alexander-shulgin-dead-godfather-of-ecstasy-and-pioneering-pharmacologist-dies-aged-88-9478223.html">Link</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com3tag:blogger.com,1999:blog-5081537833114332620.post-50204131739469813902014-04-22T14:02:00.000-07:002014-04-22T14:02:03.191-07:00Future Pharmacy: Super Nootropic - 9-Methyl-β-carboline <div style="text-align: center;">
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<a href="http://hightowerpharmacy.blogspot.com/">Read more...</a></div>
S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com26tag:blogger.com,1999:blog-5081537833114332620.post-82988170085563857462013-10-20T12:54:00.002-07:002014-11-07T12:54:32.144-08:00Gamma Oryzanol<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhI1gLO1ANjUcnZbKVXUxvvL4AnM-u9UcRRv06ywYiQcJtIFHbwtS9oplhhnjCSAa_dTh1F5APy1qib2vaYbfL2595gIeCY0fS9lbdIZo3it-mDMRZb-YrjFGzCVog4sTYN09sJaZ0y4JY/s1600/gamma.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhI1gLO1ANjUcnZbKVXUxvvL4AnM-u9UcRRv06ywYiQcJtIFHbwtS9oplhhnjCSAa_dTh1F5APy1qib2vaYbfL2595gIeCY0fS9lbdIZo3it-mDMRZb-YrjFGzCVog4sTYN09sJaZ0y4JY/s320/gamma.jpg" height="123" width="320" /></a></div>
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<b><span style="font-size: large;">Introduction</span></b><br />
Gamma Oryzanol ("Gamma-O") is a highly lipophilic sterol-like compound extracted from rice bran oil. It is used in various supplements with the belief that it increases testosterone by elevating Luteinizing Hormone (LH).<br />
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<b><span style="font-size: large;">Evidence that it increases Testosterone or LH</span></b><br />
In 1997, a placebo-controlled study was performed that examined gamma oryzanol supplementation in resistance trained men (1). The treatment group received 500 mg of gamma oryzanol for 9 weeks. Tested variables were 1 repetition max's of bench press and squat, as well as vertical jump power. No differences were seen between groups (placebo vs. gamma oryzanol). They also tested various laboratory parameters including testosterone, estrogen, cortisol, and cholesterol ratios. Again, no differences between groups were seen.<br />
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<b><span style="font-size: large;">Is Lipophilicity a Problem?</span></b><br />
Could <i>lack of absorption</i> be the reason why Gamma Oryzanol failed to effect testosterone and muscular strength in men? One of the most recent companies to market this product claims this is indeed the case. As a highly lipophilic compound, Gamma Oryzanol would need to be properly emulsified for gastrointestional absorption. A 1991 study found <5% absorption of phytosterols similar to gamma oryzanol when fed to rats by mouth (2). In order to circumvent the absorption problem, they then administered gamma oryzanol to rats through IV (intravenous) or subq (subcutaneous) and examined its effects on Luteinizing Hormone, and Growth Hormone (GH). Unexpectedly, they found that Gamma Oryzanol actually decreased LH, and GH. Interestingly, it also decreased the release of various catecholamines, including dopamine. The authors concluded:<br />
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<b><span style="font-size: large;"><i>"Although it hasn't been directly measured, this metabolic milieu...<u>may actually reduce testosterone production.</u>"</i></span></b></blockquote>
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<b><span style="font-size: large;">Summary</span></b><br />
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<ul>
<li>Gamma Oryzanol does not increase testosterone, or increase muscular strength in humans</li>
<li>In rats, IV or subq administration actually decrease testosterone and growth hormone</li>
<li>Its lack of absorption is probably a good thing</li>
</ul>
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References<br />
(1) http://www.ncbi.nlm.nih.gov/pubmed/9407258<br />
(2) http://www.ncbi.nlm.nih.gov/pubmed/1844993S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com3tag:blogger.com,1999:blog-5081537833114332620.post-34635722280221966872013-09-27T17:04:00.000-07:002014-11-07T12:54:44.066-08:00Sulbutiamine<div style="text-align: center;">
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<b><u><span style="font-size: large;">Introduction</span></u></b><br />
Sulbutiamine is a synthetic thiamine derivative designed to overcome thiamine’s inherently poor bioavailability. It was designed in the 70’s in Japan in response to widespread thiamine deficiency. Later studies revealed that it had a significant effect on treating asthenia, a type of centrally mediated fatigue.<br />
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<b><u><span style="font-size: large;">Physiochemistry</span></u></b><br />
Sulbutiamine is a lipid soluble analogue of thiamine which has been demonstrated to increase thiamine levels in tissue. Unfortunately, very little human pharmacokinetic data exists. Studies published from Servier, the French manufacturer of sulbutiamine, indicate that peak plasma levels of sulbutiamine<u>...</u><br />
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<b><i><span style="font-size: large;"><u><a href="http://www.smartpowders.com/smartside/sulbutiamine-science-2013-09.html">Read more</a></u> </span></i></b>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com0tag:blogger.com,1999:blog-5081537833114332620.post-84867678728394770502013-08-14T07:35:00.001-07:002014-11-07T12:54:52.794-08:00Galantamine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0xjdRj1DpFAPMsoolkEPqxPL23iiRrehrUzPm9Dyq9WgZHpficUogfHWZjIJFo-ZuIZRq2A1E5jpbxwiKHD20ZhkPvgn-fvBaO3-Wm0juKpq3TrQ1CWxNX6oQ2owePYmVNX9MeVAsXSI/s1600/Untitled.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0xjdRj1DpFAPMsoolkEPqxPL23iiRrehrUzPm9Dyq9WgZHpficUogfHWZjIJFo-ZuIZRq2A1E5jpbxwiKHD20ZhkPvgn-fvBaO3-Wm0juKpq3TrQ1CWxNX6oQ2owePYmVNX9MeVAsXSI/s1600/Untitled.jpg" /></a></div>
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<b><u>Galantamine</u></b> is by far my favorite nootropic. Not only is it a mild acetylcholinesterase inhibitor, it also positively modulates the alpha 7 nicotinine acetylcholine receptor. The end effect is a global increase in acetylcholine levels and the facilitation of the activation of the particular type of receptor intimately involved in learning and memory.<br />
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<b><u><span style="font-size: large;">Acetylcholinesterase (AchE)</span></u></b><br />
The strength of AchE inhibition is directly proportional to the reciprocal increase in the amount of acetylcholinesterase present. In other words, the stronger you inhibit the enzyme, the more the body produces to counteract its absence. This has been quantified in studies examining this effect with galantamine in comparison to donepezil, which saw much greater AchE enzyme elevation with donepezil. This isn't surprising since donepezil is roughly 40-300 times more potent at inhibiting this enzyme [1]. In the context of Alzheimer's disease, or other forms of dementia, this fact is relatively unimportant since the user will continue to supplement with the AchE inhibitor until death. Conversely, for a healthy individual using an AchE inhibitor for a relatively shorter amount of time, this may result in fairly significant rebound once supplementation ceases. This effect would be considerably more muted when supplementing with galantamine, especially since nootropic effects can be seen with doses much smaller then what is required to inhibit AchE.<br />
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<b><span style="font-size: large;"><a href="http://www.smartpowders.com/smartside/introducing-galantamine-2013-08.html">Continue Reading</a></span></b><br />
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References<br />
[1] <a href="http://www.ncbi.nlm.nih.gov/pubmed/15694923">http://www.ncbi.nlm.nih.gov/pubmed/15694923</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com15tag:blogger.com,1999:blog-5081537833114332620.post-63491057067660157842013-07-10T19:34:00.001-07:002022-02-22T08:06:15.136-08:00Driven Sports Craze Adulterated with Meth Analog<br />
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It has long been suspected that Driven Sports <i>Craze</i> was spiked with an unlisted stimulant, although no one could have guessed quite how sinister the stimulant would turn out to be. In light of the AX <i><a href="http://www.fda.gov/ICECI/CriminalInvestigations/ucm279679.htm" target="_blank">Slim Xtreme</a></i> controversy, it was widely assumed that if an insidious company owner would decide to spike one of their supplements, it would probably be with a non-phenylethylamine compound along the same lines as 1,3-DMAA. The latter compound is minus the benzene ring and therefore would be less likely to fall under the umbrella of the Federal Analog Act. Due to its structural dissimilarity, a non-phenyl derivative would also generate very little attention from of the FDA for at least a few years. <div>
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Not to be deterred by the thought of a lengthy prison sentence, the owner of Driven Sports decided to release an alpha-alkylated phenylethylamine nearly undetectable with most forms of drug testing. Not only does this compound produce low cross-reactivity while intact, but that its metabolites do not share overlap with conventional amphetamine metabolites - nor even ephedrine. The compound is called N, alpha-diethyl-phenylethylamine. It is 2 carbon atoms away from methamphetamine, and 1 ketone away from a popular bath salt. Overall, the alpha-ethyl substituent would produce less dopaminergic effects, while the N-ethyl group would marginally insulate the amine from rapid deamination. The end effect would be strong CNS effects, long lasting stimulation especially when coupled with caffeine, and with minimal addictive potential.. </div>
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<b><u>Background</u></b></div>
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In early 2012, Patrick Arnold tested Craze and found that it contained N-Benzyl-2-Phenylethylamine, in addition to another compound he could not positively identify without a reference (<i>more on this later</i>). When Patrick announced on various forums what he had found, he received notice from Matt Cahill's lawyers to cease public communication about Craze. </div>
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In retrospect, Matt Cahill's over-reaction to the news about Patrick's discovery should have been a huge red flag. After all, N-Benzyl-2-PEA is 1) found in nature and 2) extremely safe from being classified according to the Federal Analog Act. Instead of quieting speculation at the true contents of Craze, the legal notices simply fueled conjecture and skepticism. More importantly, however, is that the legal threats made adamant enemies out of those who would otherwise be indifferent. </div>
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<a href="http://www.mrsupplement.com.au/driven-sports-craze" rel="nofollow" target="_blank"><img src="http://cdn.mrsupplement.com.au/resources/imgs/banners/products/1363643263316.jpg" /></a></div>
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In late 2012, supplement retailers in Australia began to receive notice from the Australian government that Craze was being restricted from import due to the presence of a "methamphetamine analog." Since the notices were not public record, the Driven Sports team easily deflected the charges as based on flawed testing procedures. </div>
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Coincidentally, also during this time period, the Australian Sports Anti-Doping Authority (ASADA) banned a professional rugby player named <a href="http://www.asada.gov.au/publications/media/media_releases/asada_release_121214_Troy%20Errington_Sydney_Shield.pdf" target="_blank">Troy Errington</a> for using an extremely unique amphetamine analog that has only <a href="http://link.springer.com/article/10.1007/s11419-012-0158-1" target="_blank">rarely been referenced in the literature</a>. Interestingly enough, Mr. Errington placed blame on DS <i>Craze</i>. Indeed, Australia's <a href="http://www.smh.com.au/rugby-league/league-news/jittery-times-as-popular-workout-supplement-is-under-microscope-20130413-2hs9n.html" target="_blank"><i>National Measurement Institute</i></a> confirmed the presence of the compound in Craze. Similarly, the Swedish government banned the importation of Craze into Sweden based on independent laboratory reports from the <a href="http://www.nutraingredients.com/Industry/UPDATE-Swedish-agency-detects-legal-amphetamine-like-compounds-in-sports-supplements-not-in-authentic-Craze-says-manufacturer" target="_blank">Swedish National Lab for Forensic Science</a>. </div>
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While these stories were breaking, Patrick Arnold decided to re-test his Craze sample and match it to the referenced mass spec for this particular analog. Not surprisingly, it was a perfect match.</div>
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Driven Sports explanation for the magnitude of evidence against them involved an international counterfeiting conspiracy. (The Law of Parsimony may suggest that a counterfeiter producing a <i>more effective</i> product using a <i>nearly untraceable</i> designer stimulant is the height of absurdity, it did not detract from their legion of fans). They even had<a href="http://getds.com/20130710383/Blog/further-proof-that-craze-does-not-contain-amphetamines-part-three" target="_blank"> lab tests</a> to prove their innocence. Despite no chain of custody for these tests, the tide of public opinion was swinging back in favor for Driven Sports.</div>
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<img alt="A counterfeit warning on the Driven Sports website" src="http://www.nutraingredients.com/var/plain_site/storage/images/media/images/crazesnap/8112935-1-eng-GB/Crazesnap_dnm_full_size.jpg" style="text-align: center;" /></div>
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All of their excuses would come to light, however, when Ron Kramer of ThermoLife International would decide to <a href="http://www.thermolife.com/forum/post40648-208/" target="_blank">produce a reference standard</a> for this compound. According to Matt Cahill, the owner of Driven Sports, only <i>they</i> had a reference standard for N, alpha-diethyl-phenylethylamine, and therefore only <i>they</i> could prove or disprove its presence in Craze. (<i>Although, one might wonder why they had a reference standard for it in the first place...</i>). Now that Ron Kramer also had a reference standard, the truth could be explored more fully. No longer could Matt Cahill point towards an elaborate European counterfeiting scheme, since Ron Kramer would purchase his Craze samples <a href="http://us2.campaign-archive2.com/?u=f1d1ac0113de444f64f064618&id=ad2ef5852e" target="_blank">directly from authorized dealers</a> of Driven Sports <i>in the United States</i>.</div>
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In mid-June, Ron Kramer posted the first series of results from Craze testing:</div>
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<img src="http://i38.photobucket.com/albums/e108/ThermoThug/DSCrazeBerryLemonadeLot1211372.jpg" /></div>
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<a href="http://www.athleticx.net/articles/consumer-warning-driven-sports-craze-spiked-with-designer-stimulant/" target="_blank"><img alt="Consumer Warning: Driven Sports Craze Spiked with Designer Stimulant?" src="http://www.athleticx.net/articles/wp-content/uploads/2013/07/craze.jpg" /></a></div>
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S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com0tag:blogger.com,1999:blog-5081537833114332620.post-68457743306805198122013-05-05T16:12:00.000-07:002014-06-04T11:01:32.863-07:00Pharmacology of Hederagenin<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiUwQkVHKxI-soLUUMD4hjKuM4WIoT0m-0xDySoTJkPq7AS1Rl9s8IOIgHGilQlFE57uxv6i2QmH9LEhfIYod0vaf68XTD3J2zo-IcMCSOqL60BvilBXvh6jR75EZdC0LVbyhPPX279m_c/s1600/hederag.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiUwQkVHKxI-soLUUMD4hjKuM4WIoT0m-0xDySoTJkPq7AS1Rl9s8IOIgHGilQlFE57uxv6i2QmH9LEhfIYod0vaf68XTD3J2zo-IcMCSOqL60BvilBXvh6jR75EZdC0LVbyhPPX279m_c/s1600/hederag.jpg" /></a></div>
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<b><u>Introduction </u></b><br />
Hederagenin is a highly water insoluble triterpenoid compound that can be found in various plants including <i>Hedera helix </i>and <i>Chenopodium quinoa</i>. It has been used as a component of the <i>Fructus akebiae extract</i> (FAE) in Traditional Chinese Medicine for the treatment of depression. In rodent studies, hederagenin was identified as the active compound in FAE and was determined to have potent anti-depressant qualities.<br />
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<b><u>Hederagenin as a Psychotropic Drug </u></b><br />
In a 2010 study, Chinese researchers extracted and purified hederagenin from FAE and tested the compound on rats exposed to stress-inducing experiments [1]. As compared with the proven antidepressant escitalopram, hederagenin performed equally in reducing overt signs of stress. Additionally, hederagenin was shown to decrease biochemical markers of distress including serum ACTH and cortisol. In 2012, the same group of researchers further elucidated the mechanisms behind the antidepressant nature of hederagenin [2]. In an <i>en vitro</i> experiment, they found that hederagenin markedly inhibited the serotonin, norepinephrine, and dopamine, monoamine transporters with a Ki of 3.89±0.18 nm, 0.22±0.04 nm, and 2.87±0.54 nm, respectively. (As a comparison, cocaine is known to inhibit these transporters with a Ki of between 0.2 and 0.7 micromoles, which is several orders of magntitude less potent than hederagenin). To support their results, the researchers then used microdialysis to directly measure the CNS monoamine levels of living rats exposed to varying armounts of FAE. They found that FAE at doses of 12.6, 25, and 50 mg/kg significantly increased the extracellular concentrations of serotonin, norepinephrine, and dopamine, which would be expected with reuptake inhibition. Converting this to a Human Equivalent Dosage (HED) for a 70 kg adult equates to about 142 to 565 mg's.<br />
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<b><u>Pharmacokinetics</u></b><br />
In 2011, a benchmark study was conducted to examine the pharmacokinetics of orally administered hederagenin in rats [3]. They found that not only was hederagenin orally bioavailable, but that it successfully crossed the blood brain barrier (BBB). The former is surprising since similar compounds are known to have exceptionally poor bioavailability, even in rats.<br />
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<b><u>Physicochemical Characteristics and Kinetic Predictions</u></b><br />
Hederagenin is an acidic and hydrophobic compound with a pKa of 4.9 and a Log Sw of -6.92. It has an estimated volume of distribution (Vd) of 0.41 L/kg, an estimated GI transluminal diffusional capacity of 30-70%, and a blood brain barrier permeability coefficient (LogPS) of -3.5 [4].<br />
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<b><u>My Interpretation</u></b><br />
Most of the positive studies done on hederagenin were performed by the same institution (Southern Medical University, Guangzhou, China), and mostly by the same group of researchers [1, 2, 3]. And although I do not propose any research fabrication or bias, results this impressive should be replicated and verified. Similarly, although the rat pharmacokinetic study referenced above showed adequate bioavailability and BBB penetration, I suspect this will not be the case with humans.<br />
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<u>For example</u>:<br />
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<ul>
<li>With an estimated Vd of 0.41 L/kg, it is expected that this compound would be restricted to the total body water (TBW)</li>
<li>Acidic compounds without basic groups (pKa >6) are known to have limited distributive properties due to high-affinity binding to complexes I & II on serum albumin.</li>
<li>Based on albumin-dissociation calculations, only 0.0072% would be expected to be unbound in plasma [5], which would further restrict its Vd from the TBW to the vascular compartment.</li>
<li>Despite being highly hydrophobic (Log P: 7.08), which lends itself to BBB penetration, hederagenin would be heavily ionized in the plasma and therefore much less likely to cross the blood brain barrier.</li>
</ul>
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<b><u>Summary</u></b></div>
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Hederagenin is a very interesting compound which has demonstrated potent monoamine reuptake inhibitory properties in at least one study. These results are not exceptionally surprising since hederagenin is a component of an extract that is commonly used to treat depression in China. Unfortunately, there are no human safety or pharmacokinetic studies, and the existing en vitro and animal studies have not been independently replicated. Furthermore, the compounds chemical structure itself inspires doubt as to its true bioavailability and BBB accessibility, which I predict to be much worse. Ultimately, the studies performed on this compound to date are a great starting point but much more research is necessary to reconcile its physicochemical disparity with the remarkable effects it seems to be capable of. </div>
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<b><u>References</u></b><br />
<span style="font-family: inherit;">[1] <a href="http://www.ncbi.nlm.nih.gov/pubmed/19931301">http://www.ncbi.nlm.nih.gov/pubmed/19931301</a> </span><br />
<span style="font-family: inherit;">[2] <a href="http://www.sciencedirect.com/science/article/pii/S0091305711003236">http://www.sciencedirect.com/science/article/pii/S0091305711003236</a> </span><br />
<span style="font-family: inherit;">[3] <a href="http://www.ncbi.nlm.nih.gov/pubmed/21680262">http://www.ncbi.nlm.nih.gov/pubmed/21680262</a></span><br />
[4] <a href="http://www.ncbi.nlm.nih.gov/pubmed/9466345">http://www.ncbi.nlm.nih.gov/pubmed/9466345</a><br />
[5] <a href="http://www.pnas.org/content/82/5/1563.full.pdf">http://www.pnas.org/content/82/5/1563.full.pdf</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com10tag:blogger.com,1999:blog-5081537833114332620.post-56728812983815824872013-04-30T15:42:00.001-07:002014-06-04T11:01:32.860-07:00Is Paeonol an effective MAO inhibitor?<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhVFBs6bkD2SO6tNawgznMlnUNa_ItillbyyTMt5-sydj6COoNXsoG-qSfbN6DfQvyUZWDxVNHiqY0SvEmKh-cifFq7fwXSJUoCRcggt3TwEz_utpbzEvhySKNLn-Va5GGuZ1zbwupt0TE/s1600/paeonol.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="216" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhVFBs6bkD2SO6tNawgznMlnUNa_ItillbyyTMt5-sydj6COoNXsoG-qSfbN6DfQvyUZWDxVNHiqY0SvEmKh-cifFq7fwXSJUoCRcggt3TwEz_utpbzEvhySKNLn-Va5GGuZ1zbwupt0TE/s320/paeonol.jpg" width="320" /></a></div>
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Paeonol is a phenolic-type compound widely used as a component in Traditional Chinese Medicine (TCM). It has been reported to have analgesic, anti-inflammatory, and sedative properties. Recently Paeonol has been introduced as a Monoamine Oxidase Inhibitor in various sports supplements.<br />
<br />
Indeed in 2004, paeonol was compared against other plant-derived compounds for their ability to inhibit Monoamine Oxidase types A & B [1]. Paeonol was found to inhibit MAO-A with an IC50 of 54.6 micromoles. It also was found to inhibit MAO-B with an IC50 of 42.5 micromoles. On the surface, this may appear useful although important pharmacokinetic questions must be made. Specifically, does oral supplementation of paeonol reach a plasma concentration necessary to actually inhibit MAO?<br />
<br />
A look at the literature quickly answers this question. In 2007 a study was conducted to examine the pharmacokinetic parameters of oral paenol supplementation in humans [2]. They gave 160 mg of purified paeonal to 24 healthy individuals and found that the maximum average plasma concentration reached was 217 nanograms/mL. Converting this quantity to micromoles equals a peak plasma concentration of 0.0013 micromoles, or 33,000 times lower than the concentration necessary to inhibit 50% of MAO-B. This effectively eliminates its potential as a Monoamine Oxidase Inhibitor.<br />
<br />
<span style="font-size: large;">Summary</span><br />
<br />
<ul>
<li>Paeonol is a constituent of various types of TCM and has been recently released as a Monoamine Oxidase Inhibitor</li>
<li>Studies show that the concentration necessary to inhibit MAO-A and MAO-B are 54.6 micromoles and 42.5 micromoles, respectively.</li>
<li>Human pharmacokinetic studies indicate that the maximum plasma concentration reached with administration of 160 mg of purified paeonol is approximately thirty-three thousand times lower than what is necessary to inhibit Monoamine Oxidase, therby rendering its usefulness as a MAO inhibitor null.</li>
</ul>
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<div>
<b><u>References</u></b></div>
<div>
[1] <a href="http://www.sciencedirect.com/science/article/pii/S0378874104000431">http://www.sciencedirect.com/science/article/pii/S0378874104000431</a></div>
<div>
[2] <a href="http://www.qlhcpi.com/chengguo/lunwen_009.pdf">http://www.qlhcpi.com/chengguo/lunwen_009.pdf</a></div>
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<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com1tag:blogger.com,1999:blog-5081537833114332620.post-36453664044723053772013-03-31T14:26:00.000-07:002014-11-07T12:59:26.594-08:00Future Pharmacy III: Nobiletin<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiElrajGhRHNSl1PExLeyWPyL75-qN57-Zji2OEOg7cDueIYb8axhpYuxJ31gid7oBKDLb7u0OLgDZ5vCLwkH_8_gVeJOgtZ6ucWj1AOUJ9SyTagB7BTvO3H2ihpKgTCkmhPGhWv_CatGs/s1600/nobiletin1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiElrajGhRHNSl1PExLeyWPyL75-qN57-Zji2OEOg7cDueIYb8axhpYuxJ31gid7oBKDLb7u0OLgDZ5vCLwkH_8_gVeJOgtZ6ucWj1AOUJ9SyTagB7BTvO3H2ihpKgTCkmhPGhWv_CatGs/s320/nobiletin1.jpg" height="160" width="320" /></a></div>
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<b><u><span style="font-size: large;">Introduction</span></u></b><br />
Nobiletin is a polymethoxylated flavonoid compound extracted from the citrus peels of various fruits including the tangerine. A close chemical cousin of the well-studied tangeretin, nobiletin has potent anti-inflammatory, and anti-cancer properties. Due to its hydrophobic nature, nobiletin has been noted to have exceptional bioavailability in addition to blood brain barrier permeability. The latter is important for its novel anti-dementia, brain protective, and even nootropic characteristics.<br />
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<div style="text-align: right;">
<a href="http://hightowerpharmacy.blogspot.com/" target="_blank">Continue reading ---></a></div>
S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com9tag:blogger.com,1999:blog-5081537833114332620.post-664336075746284782013-01-19T10:11:00.000-08:002014-11-07T13:00:53.026-08:00Methoxyoctopamine: Structure & Activity<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi4BOL-Icnhec1QET1N30pp_nuXJ5GAdc8JW3QdgsvenRdhWLiOxCnm6Kv9BU4PPqrgn_sHhsgNVUFMGjlPp_YEQAqy1GLpR8kqjrnWBnuDiCWuEyCBG3pkAK0eNgF_UnKCTLhF5WWMMsA/s1600/pomoctopa.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi4BOL-Icnhec1QET1N30pp_nuXJ5GAdc8JW3QdgsvenRdhWLiOxCnm6Kv9BU4PPqrgn_sHhsgNVUFMGjlPp_YEQAqy1GLpR8kqjrnWBnuDiCWuEyCBG3pkAK0eNgF_UnKCTLhF5WWMMsA/s320/pomoctopa.jpg" height="165" width="320" /></a></div>
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<b><u>p-Methoxyoctopamine</u></b> (Para-Methoxy-Octopamine, P-OMe-Octopamine) is an interesting compound formed after en vivo hydrolysis of various natural amides such as <i>Aegeline</i> and <i>Tembamide</i>.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgKynPY6skcMqOQlQLFfMP5lXUhzB6Do8jse8Xp3YDcFuSIhCbBrQXwtNzekUkbOhdkPisZnsFonA-FSXiivoTrxCQQsb_y_0ClWvGAVfqQe2LsGfwxEMFUyv4Yppq_Cj6fDeaPzZ_SrLM/s1600/temba.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgKynPY6skcMqOQlQLFfMP5lXUhzB6Do8jse8Xp3YDcFuSIhCbBrQXwtNzekUkbOhdkPisZnsFonA-FSXiivoTrxCQQsb_y_0ClWvGAVfqQe2LsGfwxEMFUyv4Yppq_Cj6fDeaPzZ_SrLM/s1600/temba.jpg" /></a></div>
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<span style="font-size: large;"><b><u><br /></u></b></span></div>
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<span style="font-size: large;"><b><u>Structure Activity Relationships (SAR)</u></b></span></div>
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According to the marketing advertisements related to both compounds, these compounds are purported to be potent beta-agonists, and therefore suitable for inducing fat loss, as well as promoting "focus," and endowing "CNS stimulation." There is no evidence for any of these claims, although there is decades of SAR research which would contradict these statements.</div>
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<b><u>Beta-Agonism</u></b> </div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjRiSaFIrjUhQHSgLvAGct2KmBQi_vN1BDM7PJuwEJNg7ejphaEYA0krRYDXmti-dWk31cv-KsQJzO5BiW4Ih_8aEo9ogrlUjrrM5xUgeZ6sVzKfrfhWVnu25cluFld5_ZOWOY04BvUgwM/s1600/pmethoxy.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjRiSaFIrjUhQHSgLvAGct2KmBQi_vN1BDM7PJuwEJNg7ejphaEYA0krRYDXmti-dWk31cv-KsQJzO5BiW4Ih_8aEo9ogrlUjrrM5xUgeZ6sVzKfrfhWVnu25cluFld5_ZOWOY04BvUgwM/s320/pmethoxy.jpg" height="159" width="320" /></a></div>
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As has been discussed in many previous articles, methylating the para position removes beta-1 and beta-2 adrenergic affinity. This is one of the ways the body "deactivates" catecholamines with the enzyme Catechol-O-Methyl-Transferase (COMT). Since methoxyoctopamine already possesses a para-methoxy substituent, it is <i>already deactivated</i>. Conversely, a para-methoxy substituent <u>does not</u> remove beta-3 agonism. In mice and other animals, this property may confer significant fat loss potential. Unfortunately, as I mentioned in the previous article, beta-3 agonism does not promote significant fat loss in humans.</div>
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<b><u>CNS Stimulation</u></b></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKFunV81_z_mGeFNjxO_0o3HK41FfFywSehmOXkbeLtq5gAvc77xaxnSFm3c7JjGLjUSzE8CA0SG5Aent6swJWS7DtCU6Bjh05TGOuYRVn1IhlxFZpf0KkmWeorEMUoSeQHuFlTBc56FU/s1600/betahydroxy.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKFunV81_z_mGeFNjxO_0o3HK41FfFywSehmOXkbeLtq5gAvc77xaxnSFm3c7JjGLjUSzE8CA0SG5Aent6swJWS7DtCU6Bjh05TGOuYRVn1IhlxFZpf0KkmWeorEMUoSeQHuFlTBc56FU/s1600/betahydroxy.jpg" /></a></div>
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P-OMe-Octopamine also possesses a hydroxy (-OH) subsituent on the beta carbon. This substituent effectively eliminates significant CNS penetration, and therefore would remove "CNS stimulation" as a potential effect of the drug. Conversely, the para-methoxy substituent actually promotes BBB penetration, and therefore would allow CNS penetration <i>in the absence of the beta-OH</i>. Unfortunately, the effects of CNS penetration would only be negative (i.e. dysphoria) and so the lack of CNS penetration is probably a good thing (See Para-methoxyamphetamine). </div>
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<b><u>Releasing</u></b></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhGNL9-URIbvQ7XKEKaI48nxHOCuE70vCs_JV_WYToOR9V9B-6jQpI32NAp7nQzNNbbMnqc7o3_fXoSFcugIGNiGmLI5QQfQwhTU6OmzgQBLnzj0nJEQcGzXswNLW5QgF2X1c-qoqmEBZM/s1600/primarypea.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhGNL9-URIbvQ7XKEKaI48nxHOCuE70vCs_JV_WYToOR9V9B-6jQpI32NAp7nQzNNbbMnqc7o3_fXoSFcugIGNiGmLI5QQfQwhTU6OmzgQBLnzj0nJEQcGzXswNLW5QgF2X1c-qoqmEBZM/s320/primarypea.jpg" height="172" width="320" /></a></div>
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Since methoxyoctopamine is a primary phenylethylamine, it <i>may</i> still retain properties related to catecholamine releasement (See the <a href="http://hightowerpharmacology.blogspot.com/2011/06/13-dimethylamylamine.html" target="_blank"><i>Pharmacology of 1,3-DMAA</i></a>). This effect may allow a transient dumping of synaptic norepinephrine which may manifest as symptoms of the adrenergic cascade (tachycardia, tachypnea, hypertension). In contrast to 1,3-DMAA which probably has significant BBB penetration, methoxyoctopamine would not produce the "positives" of catecholamine releasement such as true CNS stimulation, and focus. The effects produced by methoxyoctopamine would probably be similar to those produced by N-methyltyramine, albeit relatively weaker due to the para-methoxy substituent.</div>
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<b><u><span style="font-size: large;">Summary</span></u></b></div>
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</div>
<ul>
<li>Para-Methoxy-Octopamine formed after en vivo hydrolysis of Aegeline and Tembamide.</li>
<ul>
<li>The para-methoxy substituent removes beta-1 and beta-2 adrenergic receptor affinity, although still allowing for the possibility of beta-3 receptor affinity.</li>
<ul>
<li>No ability to induce lipolysis (fat loss) in humans</li>
</ul>
<li>The beta-OH removes substantial CNS penetration.</li>
<ul>
<li>No ability to produce CNS stimulation.</li>
</ul>
<li><i>May</i> still retain catecholamine releasing potential, allowing for transient peripheral stimulation.</li>
<ul>
<li>Much better alternatives exist.</li>
</ul>
</ul>
</ul>
S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com3tag:blogger.com,1999:blog-5081537833114332620.post-78946653059608852752013-01-08T19:07:00.000-08:002014-05-12T06:56:19.887-07:00New "Anabolic:" Aegeline<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgDirCS2jojMnCXTe7tD6xIUoY8EY7luW-znLhCc6f8-ns3AjyGWjjLWPWT3ZlkPEkuul7O6pHG7wk8un8DxxQn6LqrxxAYbCCS1y5sJsU9wqCOk7qsZQSfpRNclJeKJPEM5_UGZkXs7jw/s1600/aegeline.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="127" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgDirCS2jojMnCXTe7tD6xIUoY8EY7luW-znLhCc6f8-ns3AjyGWjjLWPWT3ZlkPEkuul7O6pHG7wk8un8DxxQn6LqrxxAYbCCS1y5sJsU9wqCOk7qsZQSfpRNclJeKJPEM5_UGZkXs7jw/s400/aegeline.jpg" width="400" /></a></div>
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<b><span style="font-size: large;"><u>Introduction</u></span></b><br />
<b>Aegeline</b> (<i>N-[2-hydroxy-2(4-methoxyphenyl) ethyl]-3-phenyl-2-propenamide</i>) is the latest attempt by the supplement industry to produce a natural "anabolic." This compound, extracted from Aegle marmelos Correa, is the para-methoxy derivative of N-Cinnamoyloctopamine, a common food additive.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj2gAHg54Bs3FOnlLPPvTZPP68Mxh6aa9HvrX3dtkvNoypmZBdboQ1Ox72372ZdJIo9MZ9iC9GEzDtyLGsFkskNseVw4i7rR31t_UokUiwR5t_2HTbMiCJy-N87dGY4vawS4Jh967c-9vo/s1600/foodaddjpg.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="203" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj2gAHg54Bs3FOnlLPPvTZPP68Mxh6aa9HvrX3dtkvNoypmZBdboQ1Ox72372ZdJIo9MZ9iC9GEzDtyLGsFkskNseVw4i7rR31t_UokUiwR5t_2HTbMiCJy-N87dGY4vawS4Jh967c-9vo/s320/foodaddjpg.jpg" width="320" /></a></div>
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As is the case with most other secondary amides, this compound will be metabolized in the liver into two different species: phenylacrylic acid, and para-methoxy-octopamine. The rate at which these two species are created is presently unknown.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg5thf5QwvcIv7e_PsUFDVjBIh2eHgl88JeQjNMfsP8TCx4_O-9Q5GAvCK7DiD7D2g7a97Y1Y-Cg2ceZvJHYWbBpNfY9NUHqCq50zaVWIYGOF4-38r58__T6YRrj-mdE8GRjE23tfnFq68/s1600/octopa1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg5thf5QwvcIv7e_PsUFDVjBIh2eHgl88JeQjNMfsP8TCx4_O-9Q5GAvCK7DiD7D2g7a97Y1Y-Cg2ceZvJHYWbBpNfY9NUHqCq50zaVWIYGOF4-38r58__T6YRrj-mdE8GRjE23tfnFq68/s1600/octopa1.jpg" /></a></div>
<b style="font-size: x-large; line-height: 17px;"><u>Pharmacology</u></b><br />
<span style="line-height: 17px;">In the <i>murine model of diabetes</i>, aegeline was shown to decrease blood sugar at a dose of 100 mg/kg. Converting this to HED based on BSA equals about 840 mg for a 70 kg adult human. At a human equivalent dose of about 420 mg, aegeline was demonstrated to decrease triglycerides, while improving cholesterol ratios in the <i>murine model of dyslipdemia</i> (1). The authors concluded, "<i>The reasonable mapping of [aegeline] to validated pharmacophoric hypothesis and 3D QSAR model with an estimated activity (283 nM) <u>suggest that [aegeline] might be a beta(3)-AR agonist</u>."<span style="font-family: arial, helvetica, clean, sans-serif; font-size: x-small;"> </span></i></span><span style="line-height: 17px;">A follow-up study done in 2011 by the same researchers confirmed aegelines antihyperlipidemic & antihyperglycemic properties (2). </span><br />
<span style="line-height: 17px;"><br /></span>
<span style="line-height: 17px;">These results should not be surprising as octopamine has been known for years to possess these properties (3). In fact, octopamines beta(3)-agonism was clearly elucidated as far back as 1999 (4). Unfortunately, the beta(3)-adrenergic receptor is only weakly contributatory to lipolysis in humans, and octopamine was demonstrated to possess no capacity to induce lipolysis at all (4, 5). In beta(3) insensitive animals (humans), octopamine actually induces pro-adipogenic cascades through its production of hydrogen peroxide via intracellular deamination (3). </span><br />
<span style="line-height: 17px;"><br /></span>
<span style="line-height: 17px;"><br /></span>
<span style="line-height: 17px;"><b><u><span style="font-size: large;">Summary</span></u></b></span><br />
<span style="line-height: 17px;">Aegeline may indeed possess inherent anabolism as a function of its ability to convert into an octopamine derivative. Indeed, para-methoxy-octopamine (Para-OMe-Octopamine) is one of octopamines metabolites via COMT in humans. Unfortunately, the anabolism that aegeline induces is likely restricted to adipocytes since humans are extremely insensitive to beta(3)-AR agonism. </span><br />
<span style="line-height: 17px;"><br /></span>
<span style="line-height: 17px;">In the studies in which aegeline demonstrated antihyperglycemic and antihyperlipidemic properties, the animals utilized were both murine which, as described above, are beta(3)-AR receptor sensitive. Furthermore, these animals were tested against specific disease pathologies to amplify their effects. It should go without saying that the results produced will probably not translate to humans.</span><br />
<span style="line-height: 17px;"><br /></span>
<span style="line-height: 17px;"><br /></span>
<span style="font-size: large; line-height: 17px;"><b><u>References</u></b></span><br />
<span style="line-height: 17px;">(1) http://www.ncbi.nlm.nih.gov/pubmed/17197179</span><br />
<span style="line-height: 17px;">(2) http://www.ncbi.nlm.nih.gov/pubmed/21930379</span><br />
<span style="line-height: 17px;">(3) http://jpet.aspetjournals.org/content/299/1/96.long</span><br />
<span style="line-height: 17px;">(4) http://link.springer.com/article/10.1007%2FPL00005357?LI=true</span><br />
<span style="line-height: 17px;">(5) http://www.ncbi.nlm.nih.gov/pubmed/8121236</span>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com6tag:blogger.com,1999:blog-5081537833114332620.post-7099079448437617432012-12-31T18:19:00.000-08:002014-11-07T13:01:31.649-08:00Future Pharmacy II<b><u><span style="font-size: large;">The Future of Stimulants</span></u></b><br />
With most of the better stimulants banned (Ephedra) or on the chopping block (1,3-DMAA), the supplement industry has been grasping for straws in order to produce viable stimulants for "fat burners," or pre-workout formulas. Some companies have resorted to putting massive amounts of caffeine or yohimbine in their formulas in order to induce stimulation (<i>See <a href="http://www.nutrahealthsupply.com/images/dvd/vpx%20friction%20suppfct.jpg" target="_blank">this formula</a></i>: 400 mg of caffeine per serving!). Others have resorted to using non-DSHEA approved stimulants like N-Isopropyloctopamine (<i>See <a href="http://www.nutraplanet.com/product/iforce-nutrition/new-dexaprine-60-caplets.html" target="_blank">this formula</a></i>). Still others are relying upon gimmicks like "Acacia Rigidula 98%" extracts (See <a href="http://www.cognitiveliberty.org/shulgin/adsarchive/acacia.htm" target="_blank"><i>Shulgin's</i></a> thoughts on Acacia, and<i> <a href="https://www.thieme-connect.com/ejournals/abstract/10.1055/s-0032-1321226" target="_blank">this</a></i> recent study).<br />
<br />
The introduction of N-Methyltyramine (NMT) is based mainly on deceptive marketing since NMT has been around for years as a component of Citrus aurantium (Bitter Orange). Compounds like halostachine, higenamine, and N-coumaroyldopamine, are generally well-intentioned stimulant replacements that are simply pharmacologically challenged, or are not suitable for PO (by mouth) administration. And finally, compounds like "Methylsynephrine" are misleadingly misnamed to trick people into thinking they are consuming the designer stimulant Oxilofrine (alpha-methyl-synephrine) instead of the inert beta-O-methyl-synephrine (See <a href="http://www.ncbi.nlm.nih.gov/pubmed/20643105" target="_blank"><i>this</i></a> study).<br />
<br />
Nevertheless, there are still modalities to induce stimulation that circumvent the problem posed with structural analoges of PEA (namely, the Federal Analog Act). I will briefly discuss one of these modalities below.<br />
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<b><u><span style="font-size: large;"><br /></span></u></b>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiisGknEVlR-mZCU6TcycCIPpARLy6Hk8qZ7jVEwnBBSumhCQO_zsJM6meXJ35LdUsKLBhCnKtmExMWDPI4IQUrABwoSe9I2nx24PwDL2JTfXuioEHJxKzL3ObN2JTZOehXwkVvvX_kDm8/s1600/conessine.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiisGknEVlR-mZCU6TcycCIPpARLy6Hk8qZ7jVEwnBBSumhCQO_zsJM6meXJ35LdUsKLBhCnKtmExMWDPI4IQUrABwoSe9I2nx24PwDL2JTfXuioEHJxKzL3ObN2JTZOehXwkVvvX_kDm8/s1600/conessine.jpg" /></a></div>
<b><u><span style="font-size: large;"><br /></span></u></b>
<b><u><span style="font-size: large;">Conessine</span></u></b><br />
This is a natural plant extract of <i>Holarrhena antidysenterica</i> that has the phenylethylamine pharmacophore buried deep within its steroidal structure. Although it has been used for decades as traditional Indian medicine against GI parasites, its main pharmacological intervention, for the purpose of this article, is its ability to antagonize the histamine-3 receptor (H3R) (1).<br />
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H3 antagonists have been studied for the past few decades for treating narcolepsy and ADHD since they are centrally stimulating (<i>Read more <a href="http://www.amazon.com/The-Third-Histamine-Receptor-Therapeutic/dp/1420053922/ref=sr_1_1?ie=UTF8&qid=1357002659&sr=8-1&keywords=h3+antagonists" target="_blank">here</a></i>). In fact, the H3 inverse-agonist Pitolisant was demonstrated to be effective in treating narcolepsy in patients refractory to modafinil, methylphenidate, and even amphetamine (2).<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEil3geW9hk8BsagwCihSTBsAGPB3S0wXR0KC10FrsTUp4U3g_m-TLdWVKql2uyZ65XWnpEbFOx94z5aajAlVa1LVqmU-QaPOBOPATDt32ok5zOR6Kqb5QLUDQRDhFSgGTSs3BKHZb1s52U/s1600/pitolisant.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEil3geW9hk8BsagwCihSTBsAGPB3S0wXR0KC10FrsTUp4U3g_m-TLdWVKql2uyZ65XWnpEbFOx94z5aajAlVa1LVqmU-QaPOBOPATDt32ok5zOR6Kqb5QLUDQRDhFSgGTSs3BKHZb1s52U/s320/pitolisant.jpg" height="99" width="320" /></a></div>
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Although conessine is an effective H3 antagonist with exceptional Blood Brain Barrier (BBB) penetration, it has largely been overlooked in the pharmaceutical industry due to its ability to directly agonise adrenergic receptors (3). The ultimate goal for an FDA-approved H3 antagonist medication would include wakefulness-promoting <i>without peripheral effects</i> such as hypertension, or tachycardia. For the supplement industry, however, peripheral effects could be a beneficial addition since agonising adrenergic receptors on fat cells induces lipolysis.<br />
<br />
Obstacles to producing conessine include the exceptional price of synthesis, designing an efficient extraction technique, or convincing the Chinese to manufacture it in large enough quantities to be economical. Other obstacles include its near complete lack of pharmacokinetic and human safety data. Although the latter may be extrapolated from its use as Traditional Indian Medicine, the "dose makes the poison" and purified extracts of conessine have almost certainly not been historically used.<br />
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<b><u><span style="font-size: large;">Summary</span></u></b><br />
<ul>
<li>The Federal Analog Act (FAA) limits the utility of using the phenylethylamine backbone for new or novel stimulants found in nature.</li>
<li>H3 antagonism is a novel method to induce stimulation that largely circumvents the FAA</li>
<li>Natural H3 antagonists exist such as Conessine, Verongamine, Aplysamine-1, and Carcinine, that may be useful as DSHEA-approve stimulants, although future research is needed.</li>
</ul>
<br />
<b><u><span style="font-size: large;">References</span></u></b><br />
(1) http://www.ncbi.nlm.nih.gov/pubmed/18554904<br />
(2) http://www.ncbi.nlm.nih.gov/pubmed/22356925<br />
(3) http://www.ncbi.nlm.nih.gov/pubmed/18683917S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com5tag:blogger.com,1999:blog-5081537833114332620.post-91239507786021189482012-12-29T21:18:00.001-08:002014-05-12T06:56:19.893-07:00Pharmacology of N-Acetyl-L-Tyrosine<div class="separator" style="clear: both; text-align: center;">
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<img height="244" src="http://www.lookchem.com/300w%5C2010-5%5Cde4c538c-fd02-4e31-8f2c-67a198664e79.jpg" width="400" /></div>
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<b><u><span style="font-size: large;">Introduction</span></u></b><br />
<b><u>N-Acetyl-L-Tyrosine</u></b> (N-Acetyl-Tyrosine, N-acetyltyrosine, NAT) is a novel aromatic amino acid derivative commonly found in pre-workout drinks or other ergogenic sports supplements. This compound is purported to increase the bioavailability of L-Tyrosine. It may also be formed intrahepatically by the enzyme N-acetyltransferase as a mechanism of disposing aromatic amino acids (L-Phenylalanine, L-Tyrosine, L-Dopa).<br />
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<b><u><span style="font-size: large;">Characteristics</span></u></b><br />
N-Acetyl-Tyrosine has a water solubility of 2.3 mg/ml, whereas L-Tyrosine has a water solubility of 0.49 mg/ml. Increasing a compounds water solubility is a method that may enhance bioavailability, especially if the compound is particularly insoluble. Conversely, increasing water solubility may actually negatively impact its kinetics by shortening its half-life through urinary excretion. In the case of L-tyrosine, although it has limited water solubility, it has been shown to have adequate bioavailability. In humans, doses as low as 100 mg have been shown to elevate plasma tyrosine levels for as long as 7 hours (1). Doses as high as 7 grams have produced plasma tyrosine levels 223% above baseline (2). As we will see in the next section, doses of N-Acetyl-Tyrosine as high as 5 grams have only shown an elevation of tyrosine of 25% from baseline.<br />
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<b><u><span style="font-size: large;">Pharmacokinetics</span></u></b><br />
Since NAT does not possess intrinsic pharmacological properties, the most important question is: Does this compound actually <i>become</i> L-tyrosine? The answer is yes, albeit inefficiently. The enzymes <i>Aminoacylase I-III</i> are primarily located in the kidneys and are responsible for removing the acetyl group from the tyrosine molecule (3). In 1985, a proof-of-concept rodent study was designed to determine the utility of replacing the much less soluble tyrosine, with the much more soluble NAT, for total parenteral nutrition (4). They found that, at a dose of 0.5 mmol/kg body weight, NAT infusion was "<u><i>not sufficient to increase plasma tyrosine concentrations above fasting levels</i>.</u>" Converting this dose to a Human Equivalent Dose (HED) times Body Surface Area (BSA) equals a dose of about 1.25 grams. Furthermore, the study also confirmed the inefficiency of N-acetyl removal by measuring the amount of unchanged compound in the urine. With radioactive carbon tracing, they found that 74% of the supplemented form was lost in the urine as unchanged NAT, and only 23% was lost as tyrosine. This amounts to a very inefficient intrarenal conversion rate of about 25%.<br />
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Two years later, the study was repeated <i>in humans</i>, although using much higher levels of NAT (5). In this study they compared the usefulness of N-Acetyl-Tyrosine as a more soluble amino acid precursor by infusing these compounds as an IV bolus (5 grams), or as a 4 hour IV infusion. Similar to the rodent study, they found that the NAT infusion only yielded meager increases in plasma tyrosine (up to 25% from baseline), and that the majority (56%) of NAT was excreted unchanged into the urine. The authors commented: "<i><u>We conclude that under these conditions the usefulness of NAT ... as precursors for the corresponding amino acids in humans is not apparent.</u></i>"<br />
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<span style="font-size: large;"><b><u>Blood Brain Barrier (BBB)</u></b></span><br />
One of the most discussed uses for N-Acetyl-Tyrosine on the internet concerns the elevation brain tyrosine levels. The idea is that NAT, being a precursor to L-Tyrosine, would allow for greater BBB penetration as a function of direct penetration, or by increasing plasma tyrosine pools through stepwise conversion into L-tyrosine via N-deacetylation, and therefore could be useful in increasing mood, or as a general nootropic. Unfortunately, as the former sections discuss, NAT is a very inefficient tyrosine pro-drug. With regards to the former, a 1989 study analyzed the ability of 3 different compounds in elevating central tyrosine levels when compared to tyrosine itself (6). Both O-phospho-L-tyrosine and L-tyrosine methyl ester were successfully bioequivalent to tyrosine, whereas N-Acetyl-Tyrosine was ineffective.<br />
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<b><u><span style="font-size: large;">Summary</span></u></b><br />
<br />
<ul>
<li>Inefficient pro-drug to L-tyrosine</li>
<ul>
<li>The majority of N-Acetyl-L-Tyrosine is excreted as unchanged compound</li>
<li>Doses as high as 5 grams in humans have only produced meager elevations in plasma tyrosine</li>
</ul>
<li>No BBB penetration</li>
<li>Much greater water solubility; unknown significance</li>
</ul>
<br />
<b><u><span style="font-size: large;">References</span></u></b><br />
(1) http://www.journalogy.net/Publication/11933288/l-tyrosine-ameliorates-some-effects-of-lower-body-negative-pressure-stress<br />
(2) http://www.journalogy.net/Publication/30276820/randomised-controlled-trial-of-tyrosine-supplementation-on-neuropsychological-performance-in<br />
(3) http://www.sciencedirect.com/science/article/pii/0005274478900232<br />
(4) http://www.nature.com/pr/journal/v19/n6/abs/pr19851993a.html<br />
(5) http://www.sciencedirect.com/science/article/pii/002604958990005X<br />
(6) http://onlinelibrary.wiley.com/doi/10.1111/j.2042-7158.1989.tb06368.x/abstract<br />
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<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com2tag:blogger.com,1999:blog-5081537833114332620.post-47353708674297352352012-12-20T18:58:00.001-08:002014-11-07T13:05:02.558-08:00Pharmacology of N-Methyl-Tyrosine<div class="separator" style="clear: both; text-align: center;">
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<img src="http://www.molecular-networks.com/biopath3/site_media/molimages/300oasa/N-Methyl-L-tyrosine.png" /></div>
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<b><u><span style="font-size: large;">Introduction</span></u></b><br />
<b>N-Methyl-Tyrosine (NMTyr), </b>also known as <i>Surinamine</i>, is an amino acid found in the <i>Andira</i> & <i>Rhatany</i> species of plant. This compound was recently released in a stimulant pre-workout formula as a component of the "Shred complex (1)." Ironically, N-Methyl-Tyrosine was investigated in the 1940's as an <i><b>anti</b></i>-stimulant.<br />
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<b><u><span style="font-size: large;">Pharmacokinetics</span></u></b><br />
As the name suggests, N-Methyl-Tyrosine is the N-methylated analogue of L-Tyrosine. Differing from L-Tyrosine in its pharmacokinetics however, NMTyr is unable to become hydroxylated on the meta position of the benzyl ring. This conversion would normally convert L-Tyrosine into L-Dopa via the enzyme Tyrosine Hydroxylase. In fact, N-Methyl-Tyrosine is still offered from various laboratories as a tyrosine hydroxylase inhibitor (2).<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh5WSX9mIb_ckxASZOxHYtjTp3TiR9JIl9ALZ65sq49wvJ263SrqnF4T8dOUGK6BwFUn8LqRkKFBek_o7kyKB1kgC8oilIjFY3MFY3v4EeEJLVtkJee89g68WdWnDoZqgxuoCvMKAndTJI/s1600/nmtyr.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh5WSX9mIb_ckxASZOxHYtjTp3TiR9JIl9ALZ65sq49wvJ263SrqnF4T8dOUGK6BwFUn8LqRkKFBek_o7kyKB1kgC8oilIjFY3MFY3v4EeEJLVtkJee89g68WdWnDoZqgxuoCvMKAndTJI/s640/nmtyr.jpg" height="135" width="640" /></a></div>
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Without the ability to become a true catchol, the next step would normally be decarboxylation. Unfortunately, NMTyr is not a substrate for dopa decarboxylase, and therefore is a metabolic dead-end (3).<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhgkrp4N_Aq0P_lqmPucPrWT0WbSzkQK3SDlelJxPU2L573eufJ8GSbelBmxBIcPKHtf-tfx9WinTyGUChqgdQwYT92mXWEwGzkEVKbgunrB7GicuFUjy4Mo64H2GN5NVWgRfm5TgB2IZw/s1600/dopasur.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhgkrp4N_Aq0P_lqmPucPrWT0WbSzkQK3SDlelJxPU2L573eufJ8GSbelBmxBIcPKHtf-tfx9WinTyGUChqgdQwYT92mXWEwGzkEVKbgunrB7GicuFUjy4Mo64H2GN5NVWgRfm5TgB2IZw/s400/dopasur.jpg" height="247" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><i>The production of CO2 is an indicator of decarboxylase activity. N-methyl-tyrosine is unreactive.</i></td></tr>
</tbody></table>
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<b><u><span style="font-size: large;">Pharmacodynamics</span></u></b><br />
N-Methyl-Tyrosine possesses a carboxylic acid on the alpha carbon which prevents direct adrenergic receptor binding, in addition to deamination throught steric hindrance. The former modality creates a physiologic receptor antagonist via the law of mass action and vesicular depletion, and the latter increases its half-life, extending its enzymatic inhibition for a longer period of time. Even in the unlikely event of decarboxylation, NMTyr would simply yield non-beta-hydroxylated, para-hydroxylated, metabolites including NMT, which would only excacerbate its anti-adrenergic potential.<br />
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<b><u><span style="font-size: large;">Summary</span></u></b><br />
<br />
<ul>
<li><i>Anti-Stimulant</i></li>
<ul>
<li><u>Inhibits Tyrosine hydroxylase</u> - Decreases the natural production of catecholamines/neurotransmitters</li>
<li><u>Not a substrate for Dopa decarboxylase</u> - No potential for metabolic improvement</li>
<li><u>Competes for neuronal vesicular uptake with viable precursors</u> (L-tyrosine, L-dopa, L-Phenylalanine) - Physiologic competitive antagonist</li>
</ul>
</ul>
<br />
<br />
<b><u>References</u></b><br />
(1) http://directnutrition.com.au/media/wysiwyg/Albuterex_-_Nutritional_Info.jpg<br />
(2) http://www.chemicalbook.com/ChemicalProductProperty_DE_CB2212948.htm<br />
(3) http://jp.physoc.org/content/101/3/337.full.pdf<br />
<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com1tag:blogger.com,1999:blog-5081537833114332620.post-85527213447532125992012-09-02T12:16:00.001-07:002014-05-12T06:56:19.890-07:00Future Pharmacy: Amentoflavone<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiuoWM5yIqV543yJZviD4hWpzsn7IiLxlAdklLXaR5TZmV6jAk8W1P_pkxRoQ6wz28i0kEF0SLIjH0yiSJsu-e5pEOM8eIYJWye2ymbft6P78ZtFMgZKgLof_W22lXfDcw9-w_410_g_OQ/s1600/amentoflavone.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="145" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiuoWM5yIqV543yJZviD4hWpzsn7IiLxlAdklLXaR5TZmV6jAk8W1P_pkxRoQ6wz28i0kEF0SLIjH0yiSJsu-e5pEOM8eIYJWye2ymbft6P78ZtFMgZKgLof_W22lXfDcw9-w_410_g_OQ/s320/amentoflavone.jpg" width="320" /></a></div>
<br />
<strong><u>Introduction</u></strong><br />
Amentoflavone is a polyphenolic compound extracted from many different plants including Ginkgo biloba and St John's Wort. It has received most of its attention due to its anti-cancer and anti-microbial properties. This article will focus on its lesser known mechanisms which are more relevant in the context of athletic performance.<br />
<br />
<br />
<strong><u>Background</u></strong><br />
I first became aware of amentoflavone in 2005 when a research article was published demonstrating its ability to negatively modulate the benzodiazepine GABA(A) receptor site (1). This modality is a potential way to enhance learning and memory since it would disinhibit excitatory neurotransmission. It could also increase the production of testosterone by inducing the release of GnRH at the hypothalamus. Unfortunately, as its structure should remind us, amentoflavone has almost no capacity to cross the blood brain barrier as was demonstrated in the 2008 study by Colovic et al (2). This is not necessarily terrible news, as GABA(A) antagonism brings along with it a host of potentially dreadful side effects from anxiety to the potential for neurotoxicity. Luckily, its peripheral properties are significant enough to warrant further investigation.<br />
<br />
<br />
<strong><u>Phosphodiesterase Inhibition</u></strong> <br />
Phosphodiesterase (PDE) is an intracellular enzyme which degrades the second messengers cAMP or cGMP. In human adipose tissue, beta-2 agonism results in an increase in cAMP which activates lipases that cause cellular fat breakdown ("lipolysis"). By inhibiting the particular phosphodiesterase isoenzyme (PDE3) found in adipose tissue, a compound could theoretically synergize with the adrenergic signaling cascade and induce significant fat loss. Indeed, amentoflavone has demonstrated this capacity in a 1998 Italian study examining the effect of Ginkgo biloba on rat adipose tissue (3).<br />
<blockquote class="tr_bq">
<em>This work compares the inhibition of cAMP-phosphodiesterase in rat adipose tissue by a mixture of Ginkgo biloba biflavones with the effect of individual dimeric flavonoids. The degree of enzyme inhibition by G. biloba biflavones was amentoflavone > bilobetin > sequoiaflavone > ginkgetin = isoginkgetin.</em> </blockquote>
A 2006 Planta Medica article also identified amentoflavone as a weak inhibitor of PDE5, although having much greater inhibitory capacity for other isoforms (<a href="http://www.ncbi.nlm.nih.gov/pubmed/16557462">4</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/17893835">5</a>). The former PDE is responsible for the metabolism of cGMP, whereas the latter isoforms deal mainly with cAMP. Inhibiting cGMP disposal allows for vascular dilation (i.e. Viagra) via smooth muscle relaxation. Inhibiting cAMP metabolism potentiates various transduction cascades including lipolysis in adipose tissue, as discussed above, and enhancing cardiac contractility and speed (<a href="http://www.ncbi.nlm.nih.gov/pubmed/11853165">6</a>).<br />
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<br />
<strong><u>Muscular Strength</u></strong><br />
Amentoflavone was recently demonstrated to possess acetylcholinestase inhibiting properties in a 2011 study (<a href="http://www.ncbi.nlm.nih.gov/pubmed/21186982">7</a>). By inhibiting AchE, more acetylcholine ligand would be available at the neuromuscular junction, disinhibiting Ach metabolism from being a rate limiting step for muscular contraction. Unfortunately, AchE inhibition alone has not demonstrated an ability to enhance muscular strength in healthy individuals (<a href="http://www.ncbi.nlm.nih.gov/pubmed/1647337">8</a>). Fortunately, however, amentoflavone possesses another modality that may synergize well with AchE inhibition: enhancing calcium release from the sarcoplasmic reticulum.
<br />
<blockquote class="tr_bq">
<em>The Ca2+ -releasing activity of <span class="highlight">amentoflavone</span> was approximately 20 times more potent than that of caffeine...These results suggest that <span class="highlight">amentoflavone</span>, which does not contain a nitrogen atom, probably binds to the caffeine-binding site in Ca2+ channels and thus potentiates Ca2+ -induced Ca2+ release from the heavy fraction of fragmented sarcoplasmic reticulum.</em> </blockquote>
This is a novel mechanism for enhancing muscular contraction and one of the ways in which caffeine increases strength, albeit weakly (<a href="http://www.ncbi.nlm.nih.gov/pubmed/22728413">9</a>). Since amentoflavone is approximately 20 times more potent then caffeine, it is also possible that it could exert greater efficacy in this area.<br />
<br />
<strong><u>Other Mechanisms</u></strong><br />
Amentoflavone, in addition to its exceptionally weak ability to inhibit fatty acid synthase (<a href="http://www.ncbi.nlm.nih.gov/pubmed/19652385">10</a>) and ability to potentiate cAMP in adipose tissue, also possesses another novel metabolic mechanism: Protein tyrosine phosphatase 1B (PTP1B) inhibition (<a href="http://www.ncbi.nlm.nih.gov/pubmed/17268085">11</a>). <br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><img height="221" id="il_fi" src="http://www.nature.com/embor/journal/v4/n11/images/embor7400009-f3.jpg" style="margin-left: auto; margin-right: auto; padding-bottom: 8px; padding-right: 8px; padding-top: 8px;" width="400" /></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;"><em>Regulation of protein phosphatases in disease and behaviour</em>; </span><span style="font-size: xx-small;"><span class="i">EMBO reports</span> (2003) <span class="b">4</span>, 1027 - 1031 </span><span class="doi"><span style="font-size: xx-small;"><abbr title="Digital Object Identifier">doi</abbr>:10.1038/sj.embor.7400009</span></span></td></tr>
</tbody></table>
PTP1B is an negative regulator of the growth promoting cascade induced by tyrosine kinase receptors. By inhibiting PTP1B, amentoflavone disregulates the downstream pathways activated by various ligands, including those induced by insulin. This could have an exceptionally beneficial effect in relation to insulin insensitivity, or just as a means to potentiate insulin itself. Unfortunately, it could also have pro-oncogenic outcomes in those with cancer. Needless to say, <em>any</em> growth promoting compound (estrogen, GH, IGF-1, DHT, et cetra) has the capacity to stimulate oncogenesis, and so this mechanism should not be hysteria-provoking - especially in light of amentoflavones other anti-cancer modalities (anti-mutagenesis, anti-angiogenesis).<br />
<br />
<strong><u>Summary</u></strong><br />
<ul>
<li>PDE inhibition (multiple isoforms)</li>
<ul>
<li>Weakly vasodilatory</li>
<li>Capacity to potentiate adrenergic signaling in adipose tissue --> enhanced lipolysis</li>
</ul>
<li>Acetylcholinesterase inhibition</li>
<ul>
<li>Increased availability of acetylcholine at the NMJ</li>
</ul>
<li>Enhancing the release of Ca2+ from the sarcoplasmic reticulum</li>
<ul>
<li>Increased contractility of skeletal muscle</li>
</ul>
<li>Inhibition of PTP1B</li>
<ul>
<li>Potentiation of insulin signaling and other growth promoting cascades (unknown tissue specificity)</li>
</ul>
</ul>
<br />
<strong><u>References</u></strong><br />
(1) <a href="http://www.sciencedirect.com/science/article/pii/S0014299905006746">http://www.sciencedirect.com/science/article/pii/S0014299905006746</a><br />
(2) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19356077">http://www.ncbi.nlm.nih.gov/pubmed/19356077</a><br />
(3) <a href="http://www.ncbi.nlm.nih.gov/pubmed/9834158">http://www.ncbi.nlm.nih.gov/pubmed/9834158</a><br />
(4) <a href="http://www.ncbi.nlm.nih.gov/pubmed/16557462">http://www.ncbi.nlm.nih.gov/pubmed/16557462</a><br />
(5) <a href="http://www.ncbi.nlm.nih.gov/pubmed/17893835">http://www.ncbi.nlm.nih.gov/pubmed/17893835</a><br />
(6) <a href="http://www.ncbi.nlm.nih.gov/pubmed/11853165">http://www.ncbi.nlm.nih.gov/pubmed/11853165</a><br />
(7) <a href="http://www.ncbi.nlm.nih.gov/pubmed/21186982">http://www.ncbi.nlm.nih.gov/pubmed/21186982</a><br />
(8) <a href="http://www.ncbi.nlm.nih.gov/pubmed/1647337">http://www.ncbi.nlm.nih.gov/pubmed/1647337</a><br />
(9) <a href="http://www.ncbi.nlm.nih.gov/pubmed/22728413">http://www.ncbi.nlm.nih.gov/pubmed/22728413</a><br />
(10) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19652385">http://www.ncbi.nlm.nih.gov/pubmed/19652385</a><br />
(11) <a href="http://www.ncbi.nlm.nih.gov/pubmed/17268085">http://www.ncbi.nlm.nih.gov/pubmed/17268085</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com11tag:blogger.com,1999:blog-5081537833114332620.post-71475430890493101532012-06-11T10:43:00.000-07:002014-11-07T13:04:38.961-08:00Pharmacology of N-Isopropyloctopamine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhxYQG1nqAFW8eXrM50SGa4JMLrc5iFwGETvcTQBnJ5VGizBEwR-h-JlLJFijS_s-v4zOrPIBzHogiE3b-PByYJWHT_z7N3h_kKJq60NQE8MuHXJPj4EFFxLezF_ssXFWVj9xE4YkgiYH8/s1600/isopropyl.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhxYQG1nqAFW8eXrM50SGa4JMLrc5iFwGETvcTQBnJ5VGizBEwR-h-JlLJFijS_s-v4zOrPIBzHogiE3b-PByYJWHT_z7N3h_kKJq60NQE8MuHXJPj4EFFxLezF_ssXFWVj9xE4YkgiYH8/s320/isopropyl.jpg" height="144" width="320" /></a></div>
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<br />
<strong><u>Introduction</u></strong><br />
N-Isopropyloctopamine (Betaphrine, Isopropylnorsynephrine) is a chemically modified version of octopamine which possesses a more favorable pharmacodynamic profile. It was made famous in the 2011 study which examined the effects of Bitter Orange extracts on lipolysis. The authors noted:
<br />
<blockquote>
<b><i>...their common isopropyl derivative, isopropylnorsynephrine (also named isopropyloctopamine or betaphrine), was <u>clearly lipolytic</u>: active at 1 μg/ml and reproducing more than 60% of isoprenaline maximal effect in human adipocytes. This compound, not detected in C. aurantium, and which has few reported adverse effects to date, might be useful for in vivo triglyceride breakdown</i></b>. [1]</blockquote>
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<strong><u>Pharmacodynamics, Pharmacokinetics, & Structural Activity</u></strong><br />
Before we analyze N-isopropyloctopamine, we should review its chemical cousin: Octopamine. <br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhQuVnVyk_n7eQu8NrWMICU6GL9JRZB5eBy4t_afZj_-AhlFU6ZtxIqpJzh_SJF-IozMOIqO1bxcHmgzug_SMB1RBpgBTcAL5-KVY4AyeJxtBTX0KEzP8qnZSQcVf7qSl4gLAJ8n3g8dtg/s1600/octopa.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhQuVnVyk_n7eQu8NrWMICU6GL9JRZB5eBy4t_afZj_-AhlFU6ZtxIqpJzh_SJF-IozMOIqO1bxcHmgzug_SMB1RBpgBTcAL5-KVY4AyeJxtBTX0KEzP8qnZSQcVf7qSl4gLAJ8n3g8dtg/s320/octopa.jpg" height="182" width="320" /></a></div>
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Octopamine is a very specific, and weak, beta-3-receptor agonist in mammals [2, 3]. It has no physiologic ability to activate any other adrenergic receptor. Unfortunately, its ability to activate beta3 receptors in mammals does not translate to fat loss in humans. In the study <em><span class="highlight">Selective</span> <span class="highlight">activation</span> of beta3-adrenoceptors by <span class="highlight">octopamine</span>: comparative studies in mammalian fat cells, </em>the authors revealed:<br />
<blockquote class="tr_bq">
<strong><em><span class="highlight">Octopamine</span> was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, <u>while inefficient in</u> guinea-pig or <u>human fat cells</u>, like the beta3-AR agonists.</em></strong></blockquote>
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Another study by Visentin et al. noted:<br />
<blockquote class="tr_bq">
<em><strong>Human subcutaneous adipocytes constituted another model in which octopamine hardly activated lipolysis and did not inhibit insulin action. However, octopamine was able to activate glucose uptake into these cells in an oxidation-dependent manner...</strong></em>[3]</blockquote>
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What this means is that not only was octopamine <em>not</em> able to activate any lipolysis in human fat cells, but that it was <em>distinctly lipogenic</em> by enhancing insulins ability to drive glucose into adipose tissue. <br />
<br />
<em>N-isopropyloctopamine (NIPO)</em>, on the other hand, possesses a bulky N-alkyl group which alters its receptor dynamics completely. Instead of relying on beta-3-receptor agonism for its induction of lipolysis, N-isopropyloctopamine fully agonizes the beta-1 & beta-2 receptor. <br />
<blockquote class="tr_bq">
<strong><em>This compound was a highly beta selective, direct-acting adrenergic agonist,...[and] without appreciable selectivity for either beta-1 or beta-2 receptors</em></strong> [4] </blockquote>
In humans, the beta-3 receptor is a very poor target for fat loss, whereas beta-2 agonism is more than adequate. Unfortunately, although NIPO fully agonizes beta adrenergic receptors, it is very weak: "approximately 200- and 440-fold less potent than isoproterenol. [4]" Kinetically, its bioavailability is likely extremely poor - as is the case most para-hydroxylated phenylethylamine derivatives. Similarly, the para-hydroxyl also precludes BBB penetration, and so central effects like euphoria, increased attention, or insomnia, will be absent. Lastly, although the addition of the isopropyl group extends its half-life relatively, it will still be quite low (30 min - 2 hours maximum).<br />
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<strong><u>Summary</u></strong><br />
Ultimately, N-isopropyloctopamine will not likely produce exceptional results - especially in the context of fat loss. Furthermore, although N-isopropyloctopamine is offered in various fat burning/energy suppplements, it is explicitly non-FDA and non-DSHEA approved. The good news is that it has no appreciable alpha adrenergic agonism, and so signs of symptoms of high blood pressure will likely be absent [4]. <br />
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<br />
<strong><u>References</u></strong><br />
[1] <a href="http://www.ncbi.nlm.nih.gov/pubmed/21336650">http://www.ncbi.nlm.nih.gov/pubmed/21336650</a>
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[2] <a href="http://www.ncbi.nlm.nih.gov/pubmed/8106131">http://www.ncbi.nlm.nih.gov/pubmed/8106131</a><br />
[3] <a href="http://jpet.aspetjournals.org/content/299/1/96.long">http://jpet.aspetjournals.org/content/299/1/96.long</a><br />
[4] <a href="http://www.ncbi.nlm.nih.gov/pubmed/6306210">http://www.ncbi.nlm.nih.gov/pubmed/6306210</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com6tag:blogger.com,1999:blog-5081537833114332620.post-72147844466627685872012-05-05T14:31:00.001-07:002014-06-04T11:01:59.790-07:00Pharmacology of Higenamine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhYJsdMdKP0VRF3NHnxuSFL-oy9BxXDjC3gsvH-1PLWQSpORq6n_mUweYI6zpKfwv7TOIrdFQgdAW96Wnxp5lrivHYDHO8IukNeKYMGecbrU_JBxSlLBSeZgBINpGBUroi5xoh8p2wytao/s1600/higenamineChemStructure.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" closure_uid_5vimvb="4" height="183" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhYJsdMdKP0VRF3NHnxuSFL-oy9BxXDjC3gsvH-1PLWQSpORq6n_mUweYI6zpKfwv7TOIrdFQgdAW96Wnxp5lrivHYDHO8IukNeKYMGecbrU_JBxSlLBSeZgBINpGBUroi5xoh8p2wytao/s200/higenamineChemStructure.png" width="200" /></a></div>
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<br />
<strong><u>Introduction</u></strong><br />
Higenamine (demethylcoclaurine, DMC), a <span style="font-family: Times New Roman;">tetrahydroisoquinoline-type </span>compound extracted from <em>Tinospora crispa</em> and various other plants, is the newest attempt by the supplement industry at producing a DSHEA-compliant stimulant. In contrast to N-methyltyramine, P-Phenethylbenzamide (mislabeled <strong>N</strong>-phenethylbenzamide), and N-coumaroyldopamine, higenamine actually has some potential in the context of adrenergic signaling.<br />
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<strong><u>Pharmacodynamics</u></strong><br />
In comparison to the compounds listed above, research on higenamine has produced numerous en vitro and en vivo research articles over the last few decades. Reaffirmed in the literature as recently as March 2012, higenamine was demonstrated to possess potent beta-1 and beta-2 receptor agonism [1]. Due to its ability to elevate both plasma and intracellular cAMP levels, it is also being studied for the treatment of erectile dysfunction [2]<br />
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And although the greater majority of higenamine's effects are mediated through beta receptor agonism, there is also some evidence that higenamine has some alpha-1 blocking capacity, along with weak alpha-2 agonism [3].<br />
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<strong><u>Physiology</u></strong><br />
In the March 2012 article published in the Journal of Ethnopharmacology, higenamine produced effects congruent with beta-1 agonism (increased heart rate), and beta-2 agonism (decreased Mean Arterial Pressure) in anesthetized rats [1]. The latter may also be partially attributed to its alpha-1 antagonism/alpha-2 agonism, since higenamine has previously been shown to reduce diastolic pressure [4]. Beta-receptor agonism is a known mechanism for acetylcholine (Ach) release at the Neuro-Muscular Junction (NMJ), and indeed higenamine has demonstrated this effect [5]. Increasing Ach concentration at the NMJ is an established means of increasing contractile strength of skeletal muscle. Presently, no study has been performed in the context of fat loss, and its kinetic limitations nearly preclude any <em>significant</em> lipolytic effects, despite beta agonism.<br />
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<strong><u>Pharmacokinetics</u></strong><br />
Intravenous (IV) administration of higenamine in rabbits produced a terminal half-life of approximately 22 minutes, whereas IV administration in humans produced a terminal half-life of approximately 8 minutes [6, 7]. The bioavailability of orally administered higenamine in rabbits was also determined to be between 2-5% [7]. No human bioavailability studies currently exist for oral administration, although humans have much more efficient intraluminal & intrahepatic metabolic processes, and so the oral bioavailability of higenamine should be much less then that of rabbits.<br />
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<strong><u>Structure Activity Relationships</u></strong><br />
Higenamine possesses the familiar phenylethylamine pharmacophore and so its ability to interact with adrenergic receptors should not be surprising. <br />
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Similarly, it has an alpha-methyl substituent within its piperidine conformation which should effectively inhibit deamination via MAO (See Desoxypipradrol).<br />
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Structure activity relationship studies on higenamine derivatives have revealed that the 6-OH on the tetrahydroisoquinoline skeleton is a necessary constituent for adrenergic agonism. Methylating this position completely precludes any adrenergic acitivty, and in fact, creates a physiological antagonist [8]. This is important because COMT will likely create this species as a metabolite. After 1-2 half-lives (8-16 minutes), the main physiological effect will likely come from its inhibitory metabolites, rather than the stimulatory parent compound.<br />
<br />
Higenamine, in contrast to its non-hydroxylated cousin 1-Benzyl-1,2,3,4-tetahydroisoquinoline, likely possesses limited neurotoxic characteristics due to its limited ability to enter the CNS.<br />
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<strong><u>Summary</u></strong></div>
<div class="separator" style="clear: both; text-align: left;">
Higenamine definitely has the most potential of any stimulant introduced since 1,3-DMAA. Unfortunately, as the pharmacokinetic studies validate, higenamine possesses highly reactive metabolic hydroxyl substituents which limits bioavailability, and greatly reduces its half-life. Furthermore, the hydroxyl substituents also greatly reduce BBB permeability, and therefore the CNS effects common to other phenylethylamine-piperidin analogues will be absent (Pipradrol, Methylphenidate, Desoxypipradrol). Thus, the relevancy of this compound will be hard to rationalize. </div>
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<strong><u>References</u></strong><br />
[1] <a href="http://www.ncbi.nlm.nih.gov/pubmed/22265931">http://www.ncbi.nlm.nih.gov/pubmed/22265931</a><br />
[2] <a href="http://www.ncbi.nlm.nih.gov/pubmed/21956762">http://www.ncbi.nlm.nih.gov/pubmed/21956762</a><br />
[3] <a href="http://www.chinaphar.com/1671-4083/7/208.pdf">http://www.chinaphar.com/1671-4083/7/208.pdf</a><br />
[4] <a href="http://www.ncbi.nlm.nih.gov/pubmed/11953198">http://www.ncbi.nlm.nih.gov/pubmed/11953198</a><br />
[5] <a href="http://www.ncbi.nlm.nih.gov/pubmed/11953198">http://www.ncbi.nlm.nih.gov/pubmed/11953198</a><br />
[6] <a href="http://www.ncbi.nlm.nih.gov/pubmed/21393074">http://www.ncbi.nlm.nih.gov/pubmed/21393074</a><br />
[7] <a href="http://www.ncbi.nlm.nih.gov/pubmed/8968531">http://www.ncbi.nlm.nih.gov/pubmed/8968531</a><br />
[8] <a href="https://www.jstage.jst.go.jp/article/jphs1951/50/1/50_1_75/_pdf"><span style="font-size: small;">https://www.jstage.jst.go.jp/article/jphs1951/50/1/50_1_75/_pdf</span></a><br />
[9] <a href="http://www.ncbi.nlm.nih.gov/pubmed/19384584">http://www.ncbi.nlm.nih.gov/pubmed/19384584</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com3tag:blogger.com,1999:blog-5081537833114332620.post-74231255864418286842012-04-21T18:29:00.003-07:002014-11-07T13:05:43.619-08:00New Phenylethylamine DerivativesTwo new phenylethylamine derivatives are speculated to exist on the supplement market. I will <em>briefly</em> discuss their pharmacology below.<br />
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<span style="font-size: large;"><strong>N</strong><strong>-Ethyl-2-phenylpropan-1-amine</strong></span><br />
<img border="0" src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&cid=15788198" title="zoom the structure" /><br />
Synonyms: N-ethyl-Beta-Methylphenylethylamine<br />
CID <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=15788198[uid]">15788198</a><br />
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Years ago the supplement industry released Beta-MethylPhenylethylamine (b-methyl-PEA) in an attempt to enhance the effects of phenylethylamine without impinging on the Federal Analog Act (FAA). These guidelines were developed to restrict the production of designer amphetamines through chemical manipulation. B-methyl-PEA was able to side step these guidelines, and since it was easily isolatable in various plants, its legality was rarely in question. Unfortunately, the same chemical nature which made it easily side step FAA also made it inert at even large doses. As Shulgin determined decades ago, a beta-methyl group is too far away from the nitrogen to sterically protect against MAO, and therefore the differences between regular PEA and b-Methyl-PEA are negligible.<br />
<br />
N-ethyl-Beta-Methylphenylethylamine, on the other hand, possesses a fairly bulky ethyl substituent coming off the nitrogen. This substituent should protect the nitrogen from rapid MAO deamination, and therefore prolong the drugs half life significantly (See: Amphetamine vs. N-ethylamphetamine). Pharmacodynamically, this drug will act no different then regular PEA, although its longevity will enhance its catecholamine "releasing" properties, especially with acute supplementation. Similarly, the N-ethyl group will also increase the compounds amphipathism, which may expedite CNS penetration.<br />
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<strong><span style="font-size: medium;"><span style="font-size: large;">N-Benzyl-2-phenethylamine</span> </span></strong><br />
<img border="0" src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&cid=65055" title="zoom the structure" /><br />
Synonyms: Benethamine, N-Benzyl-2-PEA<br />
CID <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=65055[uid]">65055</a><br />
<br />
Extensive research with alpha-methylated derivatives of this compound (See: Benzphetamine, N-Benzylamphetamine) indicate that the main metabolite of N-Benzyl-2-PEA will be PEA. Similar to the compound previously discussed, the N-benzyl substituent will likely enjoy a longer half life than regular PEA. It should offer more CNS penetration due to the non-polarity of the benzyl moiety. The main difference between PEA and its N-benzyl derivative is that the latter may produce a local anesthetic effect relating to sodium channel inhibition. It may also possess weak sigma receptor proclivity in addition to theoretical 5-HT(2A) agonism.<br />
<br />
In summary, these compounds may indeed be superior pharmacological derivatives of phenylethylamine, although vastly inferior to alpha-substituted analogues. N-benzyl-2-PEA is a constituent of the Erythropalum scandens species, and so is likely DSHEA compliant (1). Unfortuantely, no animal or human study exists, and the potential for negative health effects, although unlikely, are not excluded.<br />
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<span style="background-color: white; color: #222222; font-family: arial, sans-serif; font-size: x-small; line-height: 16px;">(1) Erythropalum scandens: </span><span style="color: #222222; font-family: arial, sans-serif; font-size: x-small;"><span style="line-height: 16px;">http://japsonline.com/admin/php/uploads/283_pdf.pdf</span></span><br />
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<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com8tag:blogger.com,1999:blog-5081537833114332620.post-92190667809218763532012-01-01T15:32:00.000-08:002014-08-10T17:29:48.747-07:00Pharmacology of Nootropics Volume 1<iframe allowtransparency="true" frameborder="0" id="twttrHubFrame" name="twttrHubFrame" scrolling="no" src="http://platform.twitter.com/widgets/hub.1324331373.html" style="height: 10px; position: absolute; top: -9999em; width: 10px;" tabindex="0"></iframe><br />
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<strong><u>Introduction</u></strong><br />
Piracetam is a derivative of GABA which was originally designed to be an anxiolytic. Later testing revealed that it had no sedative or GABAergic effects, however it demonstrated an ability to enhance learning and cognition in some animal models. Further studies revealed a global cerebroprotective effect in the context of dementia, hypoxia, and other brain impairments. <br />
<br />In addition to its lack of GABAergic activity, it also lacks dopaminergic, anticholinergic, and antihistaminergic activity. Its one notable receptor interaction includes glutaminergic modulation at the NMDA and AMPA receptors.<br />
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<strong><u>Pharmacodynamics</u></strong><br />
Piracetam's ability to positively modulate the glutamate NMDA channel has been known for decades, however its ability to interact with the AMPA receptor is a fairly new discovery (1). Although piracetam binds to the AMPA receptor with a much lower affinity than the ampakines or aniracetam, it can bind to multiple sites on the AMPA receptor and may potentiate the effects of these agents acting on the AMPA receptor. Similarly, positively modulating the AMPA receptor itself increases the activation of the NMDA receptor, and so piracetam can be considered to be somewhat self-potentiating.<br />
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<strong><u>CNS Activity</u></strong><br />
Although piracetam does not directly activate any receptor, it positively modulates certain CNS glutaminergic receptors through allosteric activation. Allosterism is a dynamic method of facilitating receptor activation by binding to a receptor subunit that is distant from the agonist binding site. One of the advantages of allosteric activation is that it supports receptor activation even in the presence of physiological receptor antagonists (barbiturates, benzodiazepines, alcohol). Similarly, allosterism prevents receptor over-activation in the presence of excessive agonist (glutamate). The latter characteristic is one of the modalities by which piracetam helps to prevent brain excitotoxicity in the context of hypoxia or traumatic brain injuries.<br />
<br />The NMDA receptor is a voltage-dependent ion channel that allows calcium to enter the neuron along its concentration gradient after activation by glutamate and glycine (or D-serine). Normally, this channel is blocked by a positively charged magnesium ion which is attracted to the negatively charged intracellular compartment. In order for the magnesium ion to be displaced, the intracellular environment must possess a net positive charge. <br />
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This circumstance is made possible when glutamate first activates the AMPA channel. These channels then allow the rapid influx of positively charged sodium ions which results in a temporary reversal of polarity of the intracellular compartment. </div>
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After influx through the NMDA channel, ionic calcium is able to activate various enzymes including those that increase the transcription of various genes. <br />
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<strong><u>The Theory</u></strong><br />
<span style="background-color: white;">T</span>he NMDA receptor is intricately linked to memory encoding and storage. As mentioned above, activating the receptor causes the transcription of products responsible for neuronal plasticity, growth, and survival. These include the growth hormone Brain Derived Neurotrophic Factor (BDNF) and its receptor trkB (4, 5, 6, 7). Increasing BDNF is one of the mechanisms by which antidepressants reverse depression. Similarly, agents which potentiate the NMDA receptor (via potentiating the AMPA receptor) have demonstrated cognitive enhancing abilities in normal non-human primates, as well as the ability to completely reverse sleep deprivation (8, 9). Conversely, NMDA antagonists like ketamine and phenylcyclidine are well known to disrupt cognition, and impair memory formation.<br />
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In addition to enhancing glutaminergic neurotransmission, piracetam also effects, and is effected by, the cholinergic system. This system consists of 2 families of receptors (metabotropic & ionotropic) and its ligand, acetylcholine (Ach). In dementia and cognitive decline, both types of receptors are diminished along with the production of acetylcholine. The reason for the latter is due to a generalized death of acetylcholine producing neurons in the hippocampus, and due to diminished production of the enzyme choline acetyl transferase. The latter is responsible for the reason that supplementing with acetylcholine precursors has little impact on cognition in dementia, whereas compounds that prevent the degredation of acetylcholine (Acetylcholinesterase Inhibitors) markedly improve dementia symptoms. <br />
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One of the reasons why acetylcholine is able to improve cognition and memory is due to its effects on the NMDA receptor. Specifically, agonizing the M1 acetylcholine receptor enhances the responsiveness to NMDA stimulation by causing the pre-synaptic release of glutamate (10). Similarly, agonism of nicotinic Ach (nAch) receptors on post-synaptic neurons synergizes with the AMPA receptor in reversing the polarity of the intracellular environment, thereby encouraging NMDA activation (11). The densities of both types of receptors are diminished in dementia and mild-cognitive decline. In rats, piracetam has demonstrated the ability of restoring metabotropic Ach receptors in the frontal cortex of aged rats, along with facilitating the release of acetylcholine in the hippocampus (2). In another rat experiment, combining choline and piracetam together resulted in a profound enhancement of memory formation versus either compound used alone (13).<br />
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<strong><u>The Reality</u></strong><br />
Unfortunately, piracetam has never demonstrated a clear benefit in healthy humans. Even in mice studies, young healthy animals are generally immune to the effects of piracetam (2). The reason for this dichotomy is due to piracetams low potency at the NMDA receptor, and even lower potency at the AMPA receptor. Since the NMDA receptor is reliant upon the AMPA receptor for activation, piracetam is pharmacodynamically challenged. <br />
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As recent studies have demonstrated, the <em>main</em> modality by which piracetam is now thought to enact its cerebroprotective effect is by enhancing the fluidity of the lipid bilayer; specifically, the fluidity of the mitochondrial membrane (3). The exact mechanism for this characteristic is unknown, although we do know that piracetam possesses no radical scavenging properties.<br />
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In the aged brain, complexes I and IV of the electron transport chain (ETC) become less active and result in the unchecked production of reactive oxygen species (ROS) which ends up damaging the DNA and cell membrane. Piracetam has been shown to increase the activity of both complexes and it has been suggested that this characteristic may support mitochondrial longevity.<br />
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In addition to supporting the energetic needs of the neuron, the mitochondria also regulates intracellular calcium and prevents it from activating deleterious enzymes and cascades. As discussed above, piracetam is an allosteric regulator of the NMDA channel and prevents excessive calcium influx. Similarly, by restoring the fluidity of the mitochondrial membrane, piracetam enhances the mitochondrial's ability to sequestor calcium. <br />
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The vast majority of healthy adults who use piracetam have sufficient mitochondrial membrane fluidity, and therefore piracetam's ability to enhance cognition through this mechanism is muted.<br />
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<strong><u>Enhancing the Effects of Piracetam</u></strong><br />
Piracetam has multiple known mechanisms for encouraging memory formation and cognition. Unfortunately, most of the effects are only observed in the context of abnormal brain function. Luckily, due to recent studies which have more comprehensively examined the mechanisms behind piracetam, it is possible to increase the effects of piracetam through synergisms.<br />
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As noted above, piracetam has been shown to increase the activity of Complexes I and IV of the ETC. Piracetam has also been shown to support mitochondrial longevity and function by enhancing membrane fluidity.<br />
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Coenzyme Q10 (CoQ10) is a fat soluble compound which participates in the ETC as an electron acceptor from Complex I and II. Relative deficiencies of CoQ10 have generalized deleterious effects on the body, mostly as a result of mitochondrial dysfunction. Supplemental CoQ10 has a multitude of health benefits including limiting membrane peroxidation, and reducing ROS formation. The latter two mechanisms would naturally support mitochondrial longevity and function, and synergize well with piracetam. Co-supplementing with Vitamin E helps to regenerate the active form of CoQ10, ubiquinol from its oxidized form, ubiquinone. There is also some evidence that the combination increases tissue retention of CoQ10 (14). Keep in mind that these effects would require chronic supplementation in order to be observed, and that the effects will be much more pronounced in those experiencing progressive memory decline.<br />
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The next mechanism by which piracetam may enhance cognition is by supporting cholinergic neurotransmission. Studies have shown that piracetam increases the density of metabotropic acetylcholine receptors in the cerebral cortex, and that it facilitates neuronal acetylcholine release in the hippocampus. The former mechanism may support attention and working memory through norepinephrine release and the latter may support cognition by downstream mechanisms involving the NMDA receptor. Acetyl-L-Carnitine (ALCAR) has been shown to increase the production of metabotropic glutamate receptors in various parts of the brain, although not in the hippocampus. The significance of this effect is unclear, especially in relation to cognition. One of the biggest mechanisms by which ALCAR may synergize with piracetam is by enhancing the production of acetylcholine by amplifying the enzyme <em>choline acetyl transferase</em> (15).<br />
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<br />As mentioned above, the aged and demented brain has a diminished production of choline acetyl transferase. This enzyme is responsible for converting acetylcholine precursors into acetylcholine. Without an ability to maintain an acetylcholine reserve, Ach receptors slowly down-regulate resulting in self-perpetuating cognitive deterioration. Futhermore, since Ach receptors are intimately linked to the glutaminergic system, a decrement in Ach or Ach receptors will result in diminished BDNF production, thereby removing the signal for neuronal growth and survival.<br />
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<strong><u>Summary</u></strong><br />
Piracetam is the grandfather of nootropics and has been studied for the last 50 years. The effects of piracetam are subtle, even in the context of brain pathology. There is some evidence that its beneficial effects may accumulate over longer periods of time. The dosage of piracetam required to meet the minimum threshold for physiological significance is 5 grams per day. In order to maximize the effects of piracetam, the addition of CoQ10, Vitamin E, and ALCAR, should warrant contemplation. Similarly, supplementing with a choline source (Lecithin, CDP-Choline, Alpha-GPC) is a logical assumption based on the mechanisms proposed above, in addition to the rat study which demonstrated synergism. Utilizing an acetylcholine esterase inhibitor (AchEi) is a more advanced protocol and will be discussed in the next article.<br />
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<br /><strong><u>References</u></strong><br />
(1) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872987/?tool=pubmed">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872987/?tool=pubmed</a><br />
(2) <a href="http://www.springerlink.com/content/r2n324624xt644j7/">http://www.springerlink.com/content/r2n324624xt644j7/</a><br />
(3) <a href="http://www.ncbi.nlm.nih.gov/pubmed/9037245">http://www.ncbi.nlm.nih.gov/pubmed/9037245</a><br />
(4) <a href="http://www.ncbi.nlm.nih.gov/pubmed/20095391">http://www.ncbi.nlm.nih.gov/pubmed/20095391</a><br />
(5) <a href="http://www.sciencedirect.com/science/article/pii/B9780080450469008299">http://www.sciencedirect.com/science/article/pii/B9780080450469008299</a><br />
(6) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073526/?tool=pubmed">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073526/?tool=pubmed</a><br />
(7) <a href="http://www.ncbi.nlm.nih.gov/pubmed/12663749">http://www.ncbi.nlm.nih.gov/pubmed/12663749</a><br />
(8) <a href="http://www.ncbi.nlm.nih.gov/pubmed/16104830">http://www.ncbi.nlm.nih.gov/pubmed/16104830</a><br />
(9) <a href="http://www.ncbi.nlm.nih.gov/pubmed/22054117">http://www.ncbi.nlm.nih.gov/pubmed/22054117</a><br />
(10) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC33643/">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC33643/</a><br />
(11) <a href="http://jpet.aspetjournals.org/content/280/3/1117.short">http://jpet.aspetjournals.org/content/280/3/1117.short</a><br />
(12) <a href="http://www.sciencedirect.com/science/article/pii/0091305784902168">http://www.sciencedirect.com/science/article/pii/0091305784902168</a><br />
(13) <a href="http://www.sciencedirect.com/science/article/pii/0197458081900075">http://www.sciencedirect.com/science/article/pii/0197458081900075</a><br />
(14) <a href="http://jn.nutrition.org/content/130/9/2343.short">http://jn.nutrition.org/content/130/9/2343.short</a><br />
(15) <a href="http://www.ncbi.nlm.nih.gov/pubmed/7563233">http://www.ncbi.nlm.nih.gov/pubmed/7563233</a><br />
(16) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944646/?tool=pubmed">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944646/?tool=pubmed</a>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com17tag:blogger.com,1999:blog-5081537833114332620.post-87583854420664098822011-12-14T19:04:00.000-08:002014-08-15T18:40:02.071-07:00Pharmacology of N-Coumaroyldopamine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhqxxFqBCbIrhDpkMfFgvwKSkSVAKzmLZvK8FFPxhcTrdBUQeer4o6ERrxdTIxWgrvCm79fh3H4a1h5RJhsYZz3ggS3allYkcj0wqzVIHHEDHaJbB9pxUa2yFFAigfuKgisEecEYU0bzPU/s1600/n-dopamine.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="179" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhqxxFqBCbIrhDpkMfFgvwKSkSVAKzmLZvK8FFPxhcTrdBUQeer4o6ERrxdTIxWgrvCm79fh3H4a1h5RJhsYZz3ggS3allYkcj0wqzVIHHEDHaJbB9pxUa2yFFAigfuKgisEecEYU0bzPU/s320/n-dopamine.jpg" width="320" /></a></div>
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<strong><u>Introduction</u></strong><br />
N-coumaroyldopamine is a novel phenylpropenic acid derivative extracted from <em>Theobroma cacao</em> and was recently demonstrated to agonise the beta-2 receptor en vitro (1, 2). The beta-2 receptor is the most effective mechanism for the induction of fat loss in humans, and the search for natural beta-2 agonists has developed renewed interest from supplement manufacturers.<br />
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<strong><u>Pharmacokinetics</u></strong><br />
N-coumaroyldopamine is highly susceptible to metabolism by Catechol-O-Methyl-Transferase (COMT) due to its 2 meta-phenolic hydroxyl substituents. COMT can also methylate the para positions, but with lower fidelity due to regioselectivity of the COMT isoforms. This enzyme is found in the gastrointestinal mucusoa, the liver, and the periphery, and is a very effective at deactivating catecholamines. Similarly, the phenolic hydroxyls are subject to Phase II metabolism in which the -OH groups are conjugated to more water soluble substituents for more rapid excretion.<br />
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Dobutamine, a structurally similar pharmaceutical drug used to increase cardiac contractility, is designed strickly for parental or intravenous administration due to its exceptionally poor bioavailability.<br />
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Conversely, dobutamine will not undergo hydrolysis at its amine, and is therefore actually <em>more</em> metabolically stable then N-coumaroyldopamine. Even so, dobutamines half-life is only 2 minutes due to the metabolic processes described above. <br />
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<strong><u>Dopamine Prodrug</u></strong><br />
As mentioned above, another of N-Coumaroyldopamine's metabolic pathways involves hydrolysis of its amide bond.<br />
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Due to the ubiquity of biological hydrolases, the main metabolites of N-Coumaroyldopamine will be Dopamine and a cinnamic acid analogue.<br />
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<strong><u>Pharmacodynamics</u></strong><br />
In the study which examined the adrenergic potential of various Theobroma cacao constituents, N-Coumaroyldopamine was demonstrated to possess highly specific beta-2 adrenergic potential. This is consistent with the literature with regards to the Structure Activity Relationship (SAR) of catecholamine pharmacodynamics. In its unmetabolized form, N-Coumaroyldopamine possesses (1) a meta-OH substituent which allows stronger interaction with the adrenergic receptor and (2) a bulky, fairly nonpolar, substituent coming off the nitrogen. The latter is responsible for increased beta receptor affinity (See Image below). <br />
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<strong><u>Summary</u></strong><br />
N-Coumaroyldopamine is a highly selective beta2 agonist only in its <em>unmetabolized</em> form. Unfortunately, it is exceptionally vulnerable to multiple metabolic processes which makes its ability to actually reach systemic circulation highly unlikely. As a dopamine prodrug, N-coumaroyldopamine will likely also fall short. Successful dopamine prodrugs, like Docarpamine, are generally designed to be resistant to COMT and Phase II metabolism, whereas N-coumaroyldopamine is vulnerable to both.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgVKkMzCXcr7OjNXAIPx75GFOLdRfnut4_kAePqb_MWi7YdoI6OK6qN9-gRFECoQjQrTYgNeHIMkx-VoU0vNWk2SKOu2WeD3OQeSORwdpdJIP4KIr7QUxKA29NJbwAccm99hj7KSxJaz_A/s1600/docarp.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="152" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgVKkMzCXcr7OjNXAIPx75GFOLdRfnut4_kAePqb_MWi7YdoI6OK6qN9-gRFECoQjQrTYgNeHIMkx-VoU0vNWk2SKOu2WeD3OQeSORwdpdJIP4KIr7QUxKA29NJbwAccm99hj7KSxJaz_A/s320/docarp.jpg" width="320" /></a></div>
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Moreover, the 4 hydroxyl-phenolic substituents makes the parent compound highly hydrophillic which precludes BBB penetration. Other dopamine prodrugs have been developed which seek to increase CNS penetration by increasing the amphipathic nature of the drug. For example, this carbamate ester dopamine prodrug has demonstrated exceptional BBB penetration.<br />
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Ultimately, N-coumaroyldopamine has very little potential from a pharmacokinetic standpoint, and even less from a dynamic standpoint since it will not be intact by the time it arrives at the adrenergic receptor. In the presence of a strong COMT inhibitor, this compound may effectively deliver dopamine to the peripheral vasculature, and act as a mild vasodilator - particularly in the kidney's. Its half-life may also be slightly increased with conjugation inhibitors like piperine or quercetin. Unfortunately, it will not likely deliver dopamine to the brain even in the presence of metabolism inhibitors due to the high electronegativity of the cinnamic acid region of the compound.<br />
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In conclusion, N-coumaroyldopamine has great marketing potential for companies who are trying to eliminate DMAA from their products due to the recent en vitro studies. From a pharmacological standpoint, it will undubitably fall on its face in light of the hundreds of pharmaceutical papers which have examined similar compounds for the last 50 years. <br />
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<br />
<strong><u>References:</u></strong><br />
(1) <a href="http://www.pl.barc.usda.gov/downloads/jp41.pdf">http://www.pl.barc.usda.gov/downloads/jp41.pdf</a><br />
(2) <a href="http://www.fasebj.org/content/19/6/497.full.pdf">http://www.fasebj.org/content/19/6/497.full.pdf</a><br />
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<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com2tag:blogger.com,1999:blog-5081537833114332620.post-69016124889387941212011-12-14T16:42:00.000-08:002014-08-15T18:40:02.058-07:00Pharmacology of Halostachine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhqb0x_zk4fy3f6U2OnacA5ZxPZxJNkg5TyyxwwVI4LAMsgmy-qLgapsdINqTAKoItHgyaY6HeAkV2dr2x_8pFGE-UhY1XGgPtGErj82WHIASGy3qLrlPztoayKJqPEiEIODBf4RqQEdl0/s1600/halo.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhqb0x_zk4fy3f6U2OnacA5ZxPZxJNkg5TyyxwwVI4LAMsgmy-qLgapsdINqTAKoItHgyaY6HeAkV2dr2x_8pFGE-UhY1XGgPtGErj82WHIASGy3qLrlPztoayKJqPEiEIODBf4RqQEdl0/s1600/halo.jpg" /></a></div>
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<strong><u>Introduction</u></strong>:<br />
Halostachine (N-methylphenylethanolamine) is a very mild sympathomimetic agent with partial adrenergic binding potential (1).<br />
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<span style="font-size: x-small;"><u>Figure 1</u>: <em>Halostachine demonstrating partial agonism on the beta-2 adrenergic receptor</em>. <em>ISO - Isoproterenol, EPI - Epinephrine, NE - Norepinephrine, DOP - Dopamine, SAL - Salbutamol, HAL - Halostachine.</em> (7)</span></div>
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<u><b>Physiology</b></u>:<br />
In a study utilizing dogs, intravenous administration of halostachine produced increased pupil diameter, initial tachycardia followed by bradycardia, and an elevated body temperature (2). In another study, oral administration of halostachine produced only mild effects in guinea-pigs and sheep at 100-200mg/kg (3).<br />
<br />
<u><b>Pharmacodynamics</b></u>:<br />
In an en vitro study of the pharmacodynamics and Structure Activity Relationship (SAR) of various epinephrine-like compounds, halostachine was demonstrated to be 19% as effective as epinephrine in activating the beta2 receptor. As a comparison, m-synephrine was demonstrated to be 24% as effective. Halostachine was considered to have considerably less ability to activate intracellular cAMP then all other compounds, including synephrine (See picture below)(4).<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh37tk8vvB19UVrLabRetCK60tsvZU4YN2vU8a-tJxn4OEbKtNtCCcDkAyGMOxRpuZ5LzMABcJgsoW4PVkYYtyhqZTyMa-EDuzoKFSNr7v7nu7ara85Z5oGNNmvJBgN8ypm5W7QZhnZgSI/s1600/1St94JVRsNArrrWh7vL7JIp7u0zK0t795.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="247" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh37tk8vvB19UVrLabRetCK60tsvZU4YN2vU8a-tJxn4OEbKtNtCCcDkAyGMOxRpuZ5LzMABcJgsoW4PVkYYtyhqZTyMa-EDuzoKFSNr7v7nu7ara85Z5oGNNmvJBgN8ypm5W7QZhnZgSI/s320/1St94JVRsNArrrWh7vL7JIp7u0zK0t795.jpg" width="320" /></a></div>
<br />
<strong><u>Pharmacokinetics</u></strong>:<br />
Halostachine is rapidly metabolized by MAO and has a half-life of approximately 5-10 minutes (2, 5). <br />
<br />
<br />
<b><u>Structure Activity and Summary</u></b>:<br />
In comparison to epinephrine, halostachine lacks 2 hydroxyl groups in the m- and p- position on the benzene ring. The absence of these two constituents nearly precludes it from fully activating the adrenergic receptor in its current conformation. <br />
<br />
<div style="text-align: center;">
<i>“The presence of the catechol OHs and either the β-OH or the N-CH3 was absolutely required for full activation of the receptor and for full affinity shift. (4)”</i></div>
<br />
Penetration into the CNS will also be limited due to the beta-OH, and due to the absence of an alpha-CH3 (decreased amphipathism). The most likely efficient target for this molecule is the alpha receptor, which is demonstrated above in the study on dogs. Intravenous administration produced mydriasis (alpha1), tachycardia (beta1), elevated body temperature - likely due to excessive vasoconstriction -, and a triggering of the baroreflex. This reflex is activated in response to increased arterial pressure in the absence of beta2 vasodilation. As is clearly demonstrated in the pharmacodynamic study above, halostachine has almost no ability to activate the beta2 receptor and is therefore extremely dissimilar to ephedrine. Since it has almost no capacity to induce cAMP elevation it has no purpose in a fat-loss formula, nor any supplement due to its extremely rapid metabolism. Similarly, since it is a partial-agonist, it will actually decrease adrenergic signaling in the presence of endogenous epinephrine, or exogenous ephedrine.<br />
<br />
<br />
<br />
<b><u>References</u></b>:<br />
1) <a href="http://med.stanford.edu/kobilkalab/pdf/YaoNCB06.pdf">http://med.stanford.edu/kobilkalab/pdf/YaoNCB06.pdf</a><br />
2) <a href="http://www.ncbi.nlm.nih.gov/pubmed/7120117">http://www.ncbi.nlm.nih.gov/pubmed/7120117</a><br />
3) <a href="http://www.publish.csiro.au/paper/AR9690071.htm">http://www.publish.csiro.au/paper/AR9690071.htm</a><br />
4) <a href="http://molpharm.aspetjournals.org/content/65/5/1181.long">http://molpharm.aspetjournals.org/content/65/5/1181.long</a><br />
5) <a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4P-474YK4T-8F&_user=10&_coverDate=10%2F01%2F1980&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1558085639&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2af4222c0ec505ef5b9703ccf1c546bb&searchtype=a">http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4P-474YK4T-8F&_user=10&_coverDate=10%2F01%2F1980&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1558085639&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2af4222c0ec505ef5b9703ccf1c546bb&searchtype=a</a><br />
6) <a href="http://forum.bodybuilding.com/showthread.php?t=129471983&page=1">http://forum.bodybuilding.com/showthread.php?t=129471983&page=1</a><br />
7) <a href="http://www.nature.com/nchembio/journal/v2/n8/fig_tab/nchembio801_F3.html">http://www.nature.com/nchembio/journal/v2/n8/fig_tab/nchembio801_F3.html</a><br />
<br />
<br />
<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com0tag:blogger.com,1999:blog-5081537833114332620.post-59221152240363538672011-11-30T18:15:00.000-08:002014-08-15T18:40:02.055-07:00Top 8 Worst Stimulants of All Time1. <strong><u><span style="font-size: large;">Halostachine</span></u></strong><br />
<ul><li><u>Pros</u>: None</li>
<li><u>Cons</u>: Rapid elimination (Half-life of 5-10 minutes); Partial adrenergic receptor agonism (Partial agonism = receptor antagonism in the presence of endogenous epinephrine or norepinephrine)</li>
<li><u>Reference</u>: </li>
<li>(1) <a href="http://forum.bodybuilding.com/showthread.php?t=129471983&page=1">http://forum.bodybuilding.com/showthread.php?t=129471983&page=1</a></li>
</ul><br />
2. <strong><u><span style="font-size: large;">N-Methyltyramine</span></u></strong><br />
<ul><li><u>Pros</u>: None</li>
<li><u>Cons</u>: Directly inhibits lipolysis; Converts to tyramine (primary human metabolite); Rapid elimination (Half life of ~5 minutes); Sympatholytic with chronic use; No CNS penetration</li>
<li><u>References</u>: </li>
<li>(1) <a href="http://forum.bodybuilding.com/showthread.php?t=135195431&page=1">http://forum.bodybuilding.com/showthread.php?t=135195431&page=1</a> </li>
<li>(2) <a href="http://hightowerpharmacology.blogspot.com/2011/06/new-stimulant-n-methyltyramine.html">http://hightowerpharmacology.blogspot.com/2011/06/new-stimulant-n-methyltyramine.html</a> </li>
<li>(3) <a href="http://www.ncbi.nlm.nih.gov/pubmed/21336650">http://www.ncbi.nlm.nih.gov/pubmed/21336650</a> </li>
<li>(4) <a href="http://www.hindawi.com/journals/oximed/2011/482973/">http://www.hindawi.com/journals/oximed/2011/482973/</a></li>
</ul><br />
3. <strong><u><span style="font-size: large;">Tyramine</span></u></strong><br />
<ul><li><u>Pros</u>: None</li>
<li><u>Cons</u>: Minimal bioavailability in the presence of gut lumen MAO; Converts to a false neurotransmitter (receptor antagonism) - sympatholytic with chronic supplementation; Strong pressor effect with acute supplementation; Short half life (30 minutes); Depletes vesicular catecholamines; Competitively inhibits catecholamine beta-hydroxylase; No CNS penetration</li>
</ul><br />
4. <strong><u><span style="font-size: large;">Para-Synephrine <em>("Synephrine")</em></span></u></strong><br />
<ul><li>Pros: Elimination half-life of 2-3 hours</li>
<li>Cons: No CNS penetration; 1000 times less activity than norepinephrine on the alpha adrenoreceptor; 40,000 times less activity than norepinephrine on the beta-1 adrenoreceptor</li>
<li>References: </li>
<li>(1) <a href="http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/bitterorange.pdf">http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/bitterorange.pdf</a> </li>
<li>(2) <a href="http://www.hindawi.com/journals/oximed/2011/482973/">http://www.hindawi.com/journals/oximed/2011/482973/</a></li>
</ul><br />
5. <strong><u><span style="font-size: large;">3,3'-Diiodo-L-Thyronine</span></u></strong><br />
<ul><li><u>Pros</u>: Can help manage hyperthyroidism</li>
<li><u>Cons</u>:Less than 3% of the calorigenic activity of T4; No increase in BMR (Basal Metabolic Rate) en vivo; Decreases circulating levels of T4</li>
<li><u>References</u>: <a href="http://endo.endojournals.org/content/64/1/62.short">http://endo.endojournals.org/content/64/1/62.short</a> </li>
</ul><br />
6. <strong><u><span style="font-size: large;">3,5-Diiodo-L-Thyronine</span></u></strong><br />
<ul><li><u>Pros</u>: Can help manage hyperthyroidism</li>
<li><u>Cons</u>: Goitrogenic (Directly suppresses the thyroid gland); Less than 3% of the calorigenic activity of T4; No increase in BMR en vivo; Decreases circulating levels of TSH</li>
<li><u>References</u>: </li>
<li>(1) <a href="http://endo.endojournals.org/cgi/content/abstract/64/1/62">http://endo.endojournals.org/cgi/content/abstract/64/1/62</a> </li>
<li>(2) <em>3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro.</em> Journal of Molecular Endocrinolog (1997) 19, 137-147</li>
</ul><br />
7. <strong><u><span style="font-size: large;">Hordenine</span></u></strong><br />
<ul><li><u>Pros</u>: Weak competitive inhibition of MAO-B</li>
<li><u>Cons</u>: Minimal bioavailability; Elimination half-life of 20-30 minutes; No CNS penetration</li>
</ul><br />
8. <strong><u><span style="font-size: large;">Phenylethylamine</span></u></strong><br />
<ul><li><u>Pros</u>: Transient high</li>
<li><u>Cons</u>: Rapidly metabolised (Half-life of 5-10 minutes); No direct receptor agonism; Sympatholytic with chronic supplementation; Competitive inhibitor of beta-hydroxylase</li>
</ul><br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com3tag:blogger.com,1999:blog-5081537833114332620.post-52128972362186847502011-06-29T18:08:00.001-07:002014-08-15T18:40:02.051-07:00Pharmacology of p-Synephrine<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEilgMLPzzY6IduNeyjShHa2BnAPPcZyvpyFLh54VuuqAq1KcZy7XmRAhpva1DPWldl7Wc6YWAsgPfJM0UbEkBN2TduhupX1sDqn10nvoE-X8JOGIIGgisl4R-SKsFNB4xz8NaRRuqHc-4Q/s1600/482973_fig_001.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="193" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEilgMLPzzY6IduNeyjShHa2BnAPPcZyvpyFLh54VuuqAq1KcZy7XmRAhpva1DPWldl7Wc6YWAsgPfJM0UbEkBN2TduhupX1sDqn10nvoE-X8JOGIIGgisl4R-SKsFNB4xz8NaRRuqHc-4Q/s320/482973_fig_001.jpg" width="320" /></a></div>
<br />
<strong><u>Introduction</u></strong><br />
p-Synephrine (Synephrine, Oxedrine) is a common ingredient in fat burning supplements and was made popular after the FDA's ban on ephedra. For the last 8-10 years, this compound was lambasted in the media for being dangerous and even deadly. A plethora of scientific reviews on synephrine were published in which the scientific community hysterically called for its banning due to case reports of strokes and heart attacks after individuals reported using synephrine-containing fat burners. <br />
<br />
The reviews referenced older pharmacological studies on "synephrine" which pointed out its highly vasoconstrictive nature, and therefore its ability to induce arrhythmias, strokes, and heart attacks, were all the more likely. Unfortunately, the "synephrine" they were referencing was m-Synephrine, a popular OTC nasal decongestant also known as Phenylephrine (7). <br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhJLo3sDIQLYJbqgyMvDWPfjqis8VgOCG1UL9UNyL9v6-lYNfHNwEDUObaD2p4w8ndOOORRQj-1ycG09w0evn6iG-WiIReAcviA4ErrQVD-NqwqW4GTHuyBSFebevWXGiL2gADQ1SfYjF4/s1600/p-syn+vs.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="129" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhJLo3sDIQLYJbqgyMvDWPfjqis8VgOCG1UL9UNyL9v6-lYNfHNwEDUObaD2p4w8ndOOORRQj-1ycG09w0evn6iG-WiIReAcviA4ErrQVD-NqwqW4GTHuyBSFebevWXGiL2gADQ1SfYjF4/s320/p-syn+vs.jpg" width="320" /></a></div>
<br />
m-Synephrine, in contrast to p-Synephrine, is not a natural alkaloid found in Citrus aurantium (Bitter Orange extract). The story becomes even more confusing because chemical analysis of synephrine-containing fat burners have indeed found m-Synephrine in addition to p-Synephrine (1). Whether or not these companies intentionally spiked their products, or if it was simply the result of poor quality control, the end result was almost the banning of a fairly benign compound. Luckily, a more detailed analysis of the constituents of C. aurantium has excluded m-Synephrine from its natural components. <br />
<br />
To make matters more complicated, the natural alkaloid p-Synephrine exists only as (+)-p-Synephrine, whereas synthetically produced p-Synephrine exists as a 50/50 racemic mixture of (-)/(+)-p-Synephrine. The (-)-p-Synephrine enantiomer has no activity, and it is not presently known whether this form of p-Synephrine will antagonize the more active form. In fact, the body naturally converts the more active (+)-p-Synephrine to (-)-p-Synephrine as a method of deactivation. <br />
<br />
<strong><u>Structure and Activity</u></strong><br />
p-Synephrine possesses a hydroxyl (-OH) group on the benzene ring. This substituent increases the polarity of the benzene ring which reduces blood brain barrier (BBB) penetration. Furthermore, it possesses a hydroxyl substituent on the beta carbon which also reduces BBB penetration (See Ephedrine vs. Amphetamine). The combination of both hydroxyls essentially precludes any CNS effects. <br />
<br />
Similarly, a hydroxyl group in the para position is a metabolic stepping-stone towards complete elimination. For example, the main human metabolites of amphetamine are p-hydroxyamphetamine and p-hydroxynorephedrine. Para-hydroxylation also greatly enhances its interaction with Phase II metabolism, which partially explains its shorter half-life in comparison to similar non-phenolic isomers.<br />
<br />
Finally, p-Synephrine possesses a secondary terminal-amine which generally tips the balance in favor of beta adrenergic affinity vs. alpha adrenergic affinity in comparison to its norsynephrine analogue, although studies have clearly shown that p-Synephrine is functionally inert at physiological concentrations (See Pharmacodynamics below).<br />
<br />
<strong><u>Pharmacokinetics</u></strong><br />
The half-life of p-Synephrine is between 2 to 3 hours (3). Its main metabolites will be p-hydroxymandelicaldehyde via monoamine oxidase (MOA), and conjugated products via phase II metabolism. In the past, there was speculation in the literature that p-Synephrine could be converted to Octopamine en vivo, although human studies have revealed no conversion (4). Similarly, it is conceivable that p-Synephrine could be converted to epinephrine by microsomal hydroxylase enzymes in the liver, although there has not been any direct evidence of this actually occurring (5). An oral dose of 46.9 mg has been shown to reach a maximum blood concentration of 2 ng/mL in humans (3).<br />
<br />
<strong><u>Pharmacodynamics</u></strong><br />
Despite being so closely similar in structure to m-Synephrine, p-Synephrine is exponentially weaker at agonizing adrenergic receptors. Studies have shown that p-Synephrine is essentially 50x less potent then m-Synephrine at agonizing the alpha-1 receptor (3). This is a very good characteristic since it decreases the amount of direct vasoconstriction the compound is able to achieve. Highly vasoconstrictive agents increase peripheral vascular resistence and can precipitate strokes, heart attacks, or generalized peripheral ischemia. Conversely, p-Synephrine is approximately 40,000 x less potent then norepinephrine at agonizing either the beta-1 or beta-2 receptor. The latter receptor is responsible for the vast majority of inducible lipolysis.<br />
<br />
<strong><u>Vesicular Exchange-Diffusion</u></strong><br />
Similar to other compounds discussed previously (Tyramine, Octopamine, 1,3-DMAA), p-Synephrine likely participates in vesicular exchange-diffusion with endogenous catecholamines. This means that, upon supplementation, p-Synephrine is transported into neurons and becomes packaged into vesicles near the nerve terminal. This event displaces compounds like norepinephrine and epinephrine into the synapse where they can participate in adrenergic signaling. Acute supplementation of p-Synephrine in doses greater then 50 mg has demonstrated this effect in humans (6). Although the authors of the previously mentioned study attributed the cardiovascular effects of p-Synephrine to direct agonism, a more plausible mechanism is vesicular exchange diffusion as discussed above.<br />
<br />
<strong><u>p-Synephrine and Fat Loss</u></strong><br />
As previously mentioned, the primary mechanism for fat loss in humans is by the extracellular agonism of beta-2 receptor on adipocytes. Nevertheless, a much smaller proportion can also be induced by the agonism of alpha-1, beta-1, and beta-3 receptors. Similarly, antagonizing alpha-2 receptors can potentiate the mechanism induced by beta-2 receptors. With that said, the literature is fairly clear that p-Synephrine has essentially no physiological agonism of any adrenergic receptor. <br />
<br />
In a 2011 study in which they tested p-Synephrine against human adipocytes at concentrations of up to 10,000 ng/mL, no lipolysis was observed (8). To put this into the proper context, taking ~50 mg of p-Synephrine by mouth results in a maximum blood concentration of 2 ng/mL. Obviously, 10,000 ng/mL is not achievable by oral supplementation of any amount, and so p-Synephrine can be ruled-out as a direct facilitator of fat loss. <br />
<br />
Conversely, it is plausible that p-Synephrine can enhance fat loss in other ways. For example, a Citrus aurantium extract was demonstrated to increase the thermic effect of food in women, but not men (9). Another study, published in 2011, measured the resting metabolic rate (RMR) of synephrine alone, or in combination with the bioflavonoids naringin, and hesperidin.<br />
<br />
<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiVYEDztYpRTKhqscNZwGVOhZYbWIlBRyKrF1HKttYa1dy9lXoAlMD-KWb41Xy1-OIBYcM__QQkJ00QJSlUk5S43PyPfhZ3OSlKejK0HVreYXqxeb6Lxjly0-VvipWbcc8DMRKY68_h8lc/s1600/p-syn.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="339" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiVYEDztYpRTKhqscNZwGVOhZYbWIlBRyKrF1HKttYa1dy9lXoAlMD-KWb41Xy1-OIBYcM__QQkJ00QJSlUk5S43PyPfhZ3OSlKejK0HVreYXqxeb6Lxjly0-VvipWbcc8DMRKY68_h8lc/s640/p-syn.jpg" width="640" /></a></div>
<br />
The fourth condition which combined Advantra Z (50 mg p-Synephrine), hesperidin 100 mg, and naringin 600 mg, resulted in a RMR increase of approximately 17.7 % in comparison to placebo (10). To put this into context, the combination of 70 mg caffeine and 24 mg ephedrine has been demonstrated to increase RMR 8% in comparison to placebo (11). The explanation for the increase in RMR in this p-Synephrine study is currently unknown, although it is possible that the bioflavonoids competitively inhibited Phase II metabolism to some degree, and thereby increased the amount of p-Synephrine reaching the blood stream. Whether or not these transient elevations in RMR actually translate into physiological consequence remains to be seen. It should also be noted that the makers of Advantra Z funded the study, and so bias should be entertained.<br />
<br />
<strong><u>Summary</u></strong><br />
p-Synephrine is an extracted alkaloid from Bitter orange that is commonly seen in fat loss formulas. Its popularity soared as a replacement for Ma Haung ephedra after 2004, and its history has been marked for being mistaken for m-Synephrine. Presently, only one placebo-controlled trial has been published which has examined Citrus aurantium/p-Synephrine for the end-point of weight loss (12). No clinical significance was seen.<br />
<br />
<strong><u>p-Synephrine sources (Synthetic)</u></strong><br />
1. <a href="http://www.amazon.com/gp/product/B000JX0XBE/ref=as_li_tf_tl?ie=UTF8&tag=hightowephar-20&linkCode=as2&camp=1789&creative=9325&creativeASIN=B000JX0XBE">Primaforce</a><br />
2. <a href="http://www.amazon.com/gp/product/B001P0XR7M/ref=as_li_tf_tl?ie=UTF8&tag=hightowephar-20&linkCode=as2&camp=1789&creative=9325&creativeASIN=B001P0XR7M">SNS</a><img alt="" border="0" height="0" src="http://www.assoc-amazon.com/e/ir?t=hightowephar-20&l=as2&o=1&a=B001P0XR7M" style="border: currentColor !important; margin: 0px !important;" width="0" /> <br />
<br />
<div class="separator" style="clear: both; text-align: left;">
<strong><u>References</u></strong></div>
<div class="separator" style="clear: both; text-align: left;">
(1) <a href="http://www.nature.com/ijo/journal/v29/n4/abs/0802879a.html">http://www.nature.com/ijo/journal/v29/n4/abs/0802879a.html</a></div>
<div class="separator" style="clear: both; text-align: left;">
(2) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC302343/?page=1">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC302343/?page=1</a></div>
<div class="separator" style="clear: both; text-align: left;">
(3) <a href="http://www.hindawi.com/journals/oximed/2011/482973/">http://www.hindawi.com/journals/oximed/2011/482973/</a></div>
<div class="separator" style="clear: both; text-align: left;">
(4) <a href="http://onlinelibrary.wiley.com/doi/10.1002/bmc.1705/full">http://onlinelibrary.wiley.com/doi/10.1002/bmc.1705/full</a></div>
<div class="separator" style="clear: both; text-align: left;">
(5) <a href="http://jb.asm.org/content/122/3/866.full.pdf">http://jb.asm.org/content/122/3/866.full.pdf</a></div>
<div class="separator" style="clear: both; text-align: left;">
(6) <a href="http://www.ncbi.nlm.nih.gov/pubmed/16317106">http://www.ncbi.nlm.nih.gov/pubmed/16317106</a></div>
<div class="separator" style="clear: both; text-align: left;">
(7) <a href="http://www.tampabayanalytical.com/Roman_ICSB2007.pdf">http://www.tampabayanalytical.com/Roman_ICSB2007.pdf</a></div>
<div class="separator" style="clear: both; text-align: left;">
(8) <a href="http://www.ncbi.nlm.nih.gov/pubmed/21336650">http://www.ncbi.nlm.nih.gov/pubmed/21336650</a></div>
<div class="separator" style="clear: both; text-align: left;">
(9) <a href="http://www.nature.com/oby/journal/v13/n7/abs/oby2005141a.html">http://www.nature.com/oby/journal/v13/n7/abs/oby2005141a.html</a></div>
<div class="separator" style="clear: both; text-align: left;">
(10) <a href="http://www.medsci.org/v08p0295.htm">http://www.medsci.org/v08p0295.htm</a></div>
<div class="separator" style="clear: both; text-align: left;">
(11) <a href="http://www.nature.com/oby/journal/v12/n7/full/oby2004144a.html">http://www.nature.com/oby/journal/v12/n7/full/oby2004144a.html</a></div>
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(12) <a href="http://www.ncbi.nlm.nih.gov/pubmed/15541270">http://www.ncbi.nlm.nih.gov/pubmed/15541270</a></div>S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com4tag:blogger.com,1999:blog-5081537833114332620.post-2941159397570061622011-06-26T17:29:00.000-07:002014-08-15T18:40:02.048-07:00Pharmacology of 1,3-Dimethylamylamine<div class="separator" style="clear: both; text-align: center;">
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<strong>1,3-Dimethylamylamine</strong> (DMAA, Methylhexanamine, Forthane, Geranamine) is an atypical sympathomimetic drug utilized in various sports supplements. It was originally investigated in the 1970's by the pharmaceutical company Eli Lilly as a nasal decongestant. In the original patent application, it was described as having less CNS effects then amphetamine, and less systemic symptoms then ephedrine. Also in comparison with ephedrine, it was deemed more volatile and therefore preferable in applications requiring volatility: nasal sprays, inhalers (1). In 2006, DMAA was re-released as a dietary supplement by Ergopharm (E-Pharm) in the product "AMP" as an extract of geranium oil.<br />
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<strong><u>Structure Activity Relationships</u></strong><br />
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Similar to Amphetamine, DMAA possesses a methyl substituent on the alpha-carbon which prolongs the drugs half-life by sterically interfering with monoamine oxidase. This substituent also enhances its ability to act as a catecholamine reuptake inhibitor (See <em>Reuptake Inhibition</em> below). Furthermore, an alpha methyl substituent increases the compounds amphipathism which expedites CNS penetration.<br />
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As the image below demonstrates, the requirements for a phenethylamine-type compound to directly agonise the adrenergic receptor include 1) a highly polar region most distal from the amine, and 2) a hydroxyl substituent on the beta-carbon. Furthermore, the orientation of the beta-hydroxyl group and alpha-methyl group influences its ability to directly agonize the receptor (1R,2S), versus its ability to act as a releasing agent (1S,2S). Since DMAA does not possess a polar substituent distal to the amine, nor is it able to interact with beta-hydroxylase enzymes, its ability to directly agonise the adrenergic receptor is completely eliminated. This characteristic narrows the pharmacological range of DMAA's effects to 1) reuptake inhibition and 2) catecholamine releasing.<br />
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<strong><u>Catecholamine Releasing Properties</u></strong><br />
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Although (2S)-Amphetamine is the prototypical releasing agent, the structural criteria necessary for a compound to act as a releasing agent are fairly ubiquitous for phenylethylamine-type compounds. In fact, non-phenolic alkylamines like cyclopentamine and tuaminoheptane are also known to be potent releasing agents. <br />
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In order to act as a RA, a compound must be able to diffuse into the nerve soma, or be taken up by transcellular catecholamine channels. The former requires sufficient lipophilicity, and the latter requires structural similarity to either norepinephrine or epinephrine. It should come as no surprise then that DMAA is able to perform this function based its structural similarity to amphetamine.<br />
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The primary location for peripherally-acting releasing agents is in the terminal ends of nerves extending from the sympathetic nervous system to organs such as the heart, kidney, and to nerves supplying the vasculature. In these locations, RA's cause a localized release of norepinephrine into the synapse which acts post-synaptically to increase heart rate (beta-1), cause renal vasodilation (B1), and peripheral vasoconstriction (alpha-1). To a smaller extent, RA's are able to stimulate the release of epinephrine (EP) and norepinephrine (NE) from chromaffin cells of the adrenal gland. Since epinephrine is a strong beta-2 receptor agonist, peripheral vasodilation may partly offset the vasoconstriction induced by norepinephrine which acts primarily on alpha-1 receptors.<br />
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<strong><u>Reuptake Inhibition</u></strong><br />
Reuptake inhibition is an effective mechanism for potentiating an adrenergic environment by increasing the amount of time a catecholamine has to interact with a postsynaptic receptor.<br />
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As noted above, the addition of an alpha-methyl substituent greatly increases its receptor affinity for catecholamine transporters, and therefore its ability to block both NE & EP reuptake. For example, Amphetamine, which differs from phenylethylamine (PEA) by only an alpha-methyl group, has 6 times greater affinity for NE transporters then PEA (2).<br />
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Another structural alteration which <em>decreases</em> affinity for reuptake receptors is N-methylation. For example, amphetamine has roughly 4 times greater affinity for NE channels then N-methylamphetamine. With respect to DMAA, it can be reasonably concluded that its affinity for NE channels would reside somewhere between tyramines and amphetamines based on its structural similarity to propylhexedrine (2, 3).<br />
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<strong><u>DMAA and Human Physiology</u></strong><br />
In 1948, DMAA was investigated for its effects on blood pressure and given to a single 78 kg male subject in dosages of 2 mg/kg (156 mg), and 3 mg/kg (234 mg) while fasted and at rest (4). The 2 mg/kg dosage produced elevations in systolic & diastolic blood pressure of 22 mm Hg, each, in addition to a decrement of heart rate of 8 beats per minute. The 3 mg/kg dosage produced intolerable side effects as well as an irregular heart rate.<br />
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In 2011, USP labs and the University of Memphis funded a study which examined the effects of caffeine alone, DMAA alone, or a caffeine & DMAA combination, on heart rate and blood pressure (5). The highest dose caffeine (250 mg) plus highest dose DMAA (75 mg) produced elevations of systolic pressure of 24 mm Hg, and elevations of diastolic pressure of 12 mm Hg, after 60 minutes. Heart rate decreased by 6 bpm also at 60 minutes.<br />
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These effects are congruent with the pharmacology described above. As a releasing agent, DMAA will increase the sympathetic tone resulting in generalized vasoconstriction. The best indicator of this event is by looking at its effects on diastolic blood pressure. Highly vasoconstrictive compounds like Phenylephrine profoundly impact diastolic pressure, which is a clue to the state of systemic vascular resistance. Similarly, since both studies demonstrated a negative chronotropic effect (heart rate lowering), it reaffirms the fact that DMAA possesses no tangible direct receptor agonism since it cannot overcome the baroreceptor reflex. For example, ephedrine is an effective releasing agent in addition to directly agonising beta receptors. The former modality produces elevations in systolic and diastolic blood pressure. The latter modality results in an increase in heart rate via direct beta-1/2 receptor agonism. Normally, the human body seeks to establish pressure homeostasis. When blood pressure becomes elevated for whatever reason, the heart rate decreases reflexively via vagus nerve stimulation of the heart. Norepinephrine alone is not potent enough to overcome the baroreflex, whereas epinephrine and other beta-2 agonists are; likely the result of beta-1/2 synergy in transduction mechanisms involving cAMP. Since DMAA elevates both diastolic and systolic blood pressure, while at the same time decreasing heart rate, it becomes clear that most of its pharmacodynamic processes involve norepinephrine.<br />
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<strong><u>Summary</u></strong><br />
1,3-DMAA possesses an interesting pharmacological profile with structural and physiological similarities to Amphetamine, Propylhexedrine, and Tuaminoheptane. It's main modalities are related to its ability to act as a releasing agent, and by reuptake inhibition. Although not discussed in the article above, 1,3-DMAA lacks polar constituents and therefore may have significant blood brain barrier (BBB) penetration. It may also be transported into the CNS by specific amino acid transporters. The result of these processes may produce symptoms associated with other CNS drugs (methylphenidate, amphetamine, modafinil) including alertness, insomnia, and euphoria. <br />
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Centralized effects are kinetically driven, where BBB penetration can be increased as a function of blood concentration divided by time. The quicker 1,3-DMAA is able to reach a high blood concentration, the more central effects can be anticipated. The fastest delivery methods are intranasal and intravenous, whereas the slowest delivery method is by mouth. Nevertheless, it is still possible to achieve a high blood concentration quickly by maximizing oral supplementation parameters. A solution which effectively homogenizes 1,3-DMAA is the best way to expedite gastrointestinal absorption and blood delivery. This is why products like Clearshot Concentrate<img alt="" border="0" height="1" src="http://www.assoc-amazon.com/e/ir?t=hightowephar-20&l=as2&o=1&a=B00347J3F4" style="border: currentColor !important; margin: 0px !important;" width="1" />
have demonstrated exceptional CNS effects in comparison to powders that must be mixed with water before consuming. Most of the latter do not yield homogeneous solutions, and therefore result in slower absorption and decreased CNS penetration. In the brain, DMAA would function in a similar manner to amphetamine and cause a release of both norepinephrine and dopamine. The latter compound responsible for the euphoric feelings associated with amphetamine and methamphetamine, whereas the former is responsible for an increase in alertness.<br />
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In contrast to other natural releasing agents/reuptake inhibitors like tyramine, 1,3-DMAA will not produce metabolites (octopamine; synephrine) which interefere with adrenergic signaling. Based on documented research with similar compounds, the most likely metabolites will be due to deamination, and N-methylation. Similarly, due to its alpha-methyl substituent, 1,3-DMAA probably enjoys a much longer half-life then tyramine (@ 30 min), and therefore more time to exert its influence within the body.<br />
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<strong><u>References</u></strong><br />
(1) <a href="http://worldwide.espacenet.com/publicationDetails/biblio?FT=D&date=19440530&DB=EPODOC&locale=en_EP&CC=US&NR=2350318A&KC=A">http://worldwide.espacenet.com/publicationDetails/biblio?FT=D&date=19440530&DB=EPODOC&locale=en_EP&CC=US&NR=2350318A&KC=A</a><br />
(2) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1510671/pdf/bripharmchem00016-0040.pdf">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1510671/pdf/bripharmchem00016-0040.pdf</a><br />
(3) <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1776552/pdf/brjpharm00548-0152.pdf">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1776552/pdf/brjpharm00548-0152.pdf</a><br />
(4) THE COMPARATIVE PHARMACOLOGY OF THE ISOMERIC HEPTYLAMINES’ DAVID F. MARSH<br />
(5) <a href="http://physsportsmed.org/doi/10.3810/psm.2011.09.1927">http://physsportsmed.org/doi/10.3810/psm.2011.09.1927</a><br />
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<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com9tag:blogger.com,1999:blog-5081537833114332620.post-80460580968464894662011-06-20T19:43:00.000-07:002014-08-15T18:40:02.066-07:00New Stimulant: N-MethylTyramine<div class="separator" style="clear: both; text-align: center;">
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<strong>Compound</strong>: N-MethylTyramine (4-Hydroxy-N-methylphenethylamine)</div>
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<strong>Source</strong>: Citrus aurantium</div>
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<strong>CAS</strong>: 370-98-9</div>
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<strong>Half-life</strong>: 5.6 min</div>
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<strong><u>N-MethylTyramine (NMT)</u></strong> is a new phenylethylamine derivative introduced as a replacement for 1,3-DMAA in various sports supplements. The scientific literature on this compound is sparse, and human data does not exist. Furthermore, most of the en vitro evidence suggests that it possesses the same characteristics as its chemical cousin: tyramine. This is disappointing since tyramine has an unfavorable pharmacological profile. In addition to depleting vesicular catecholamines in a reserpine-like fashion, it also converts to a false neurotransmitter (octopamine) which displaces active neurotransmitters (dopamine/EP/NE) from synaptic vesicles. Once an action potential reaches the terminal button, vesicles containing a mix of DA/NE/EP and octopamine will be deployed into the synapse. Since octopamine has almost no activity on human adrenergic receptors, it will essentially be acting as a receptor antagonist via the law of mass action. Furthermore, releasing agents are renown for increasing the oxidative potential of the extracellular environment by overloading MAO with catecholamine substrates. Unfortunately, nervous tissue is not as resilient towards oxidative stress as compared to other tissue, and so this characteristic of NMT/tyramine is an important concept to remember.</div>
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<strong><u>Primary metabolic reactions</u></strong></div>
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Contrary to popular wisdom, N-methyl derivatives of phenylethylamine are unable to be metabolized by dopamine beta-hydroxylase. This effectively renders NMT with no intrinsic ability to activate adrenergic receptors, although its ability to convert to metabolites with some activity still exists. The liver will remove the N-methyl substituent, thereby converting it to tyramine. Tyramine is likely the target compound with catecholamine-releasing properties, not NMT, and since its half-life is 6x's that of NMT, tyramine will likely have sufficient time to convert to octopamine, and thereby create an antagonistic environment towards adrenergic receptors with octopamine, a false neurotransmitter. Very little, if any, of the remaining octopamine will be converted to p-synephrine.</div>
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<strong><u>Structure Activity Relationship</u></strong><br />
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<strong><u>A</u></strong>: NMT possesses a para-hydroxyl on the benzene ring which increases the polarity of the phenyl substituent and thereby decreases lipid solubility. Ultimately this will drastically decrease blood-brain-barrier permeability, and therefore restrict significant CNS effects.</div>
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<strong><u>B1</u></strong>;<strong><u>B2</u></strong>: NMT lacks a meta-hydroxyl substituent which essentially precludes it from significant adrenergic receptor agonism even after beta-hydroxylation (i.e. conversion to p-synephrine).</div>
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<strong><u>C:</u></strong> NMT also lacks a methyl group on the alpha carbon (one carbon away form the nitrogen). This addition generally prolongs the drugs half-life by sterically interfereing with MAO, and also increases its ability to act as a DA/NE reuptake inhibitor. The absence of this substituent generally equates to rapid metabolism and elimination. This holds true for NMT which has a half-life of ~5 minutes. </div>
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<strong><u>D:</u></strong> Finally, NMT possesses an N-methyl substituent which effects the dynamics of the compound. In comparison with dopamine which mainly effects DA receptors, epinine (N-Methyldopamine) possesses both dopaminergic and adrenergic receptor agonistic properties. Similarly, NMT should (in theory) possess more observable adrenergic receptor activity when compared to tyramine, although even after beta-hydroxylation, the concentration necessary to produce significant adrenergic activity is not achievable with oral supplementation. Similarly, since NMT has to first undergo N-demethylation into tyramine, the amount of beta-hydroxylated metabolite will likely be clinically unobservable.</div>
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In summary, the pharmacology of NMT is similar to its primary amine analogue: tyramine. Differing from tyramine, however, NMT possesses an N-methyl substituent which creates a secondary amine. Based on activity-relationships of similar structural derivatives, the addition of an N-methyl substituent increases affinity for adrenergic receptors in theory, although en vivo research in humans has documented negligable activity even after beta-hydroxylation. This is compounded by the absence of a meta-hydroxyl substituent on the benzene ring. </div>
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<em>Acute</em> supplementation of NMT will likely produce symptoms relating to its catecholamine-releasing characteristics: hyperactivity/increased energy, increased heart rate, increased inotropy, with a slight pressor effect. Conversly, in the presence of a MAOI, acute supplementation may result in a toxic adrenergic crisis. Chronic supplementation with NMT will likely product symptoms of peripheral sympatholytic supplementation: hypotension, nasal congestion, syncope, and generalized muscular weakness. Ultimately, as a replacement for 1,3-DMAA, NMT is a poor choice.</div>
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<br />S.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.com8