Pharmacology of Hederagenin

Introduction 
Hederagenin is a highly water insoluble triterpenoid compound that can be found in various plants including Hedera helix and Chenopodium quinoa. It has been used as a component of the Fructus akebiae extract (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.

Hederagenin as a Psychotropic Drug 
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 en vitro 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.

Pharmacokinetics
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.

Physicochemical Characteristics and Kinetic Predictions
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].

My Interpretation
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.

For example:

• With an estimated Vd of 0.41 L/kg, it is expected that this compound would be restricted to the total body water (TBW)
• 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.
• 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.
• 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.

Summary

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. 

References
[1] http://www.ncbi.nlm.nih.gov/pubmed/19931301 
[2] http://www.sciencedirect.com/science/article/pii/S0091305711003236 
[3] http://www.ncbi.nlm.nih.gov/pubmed/21680262
[4] http://www.ncbi.nlm.nih.gov/pubmed/9466345
[5] http://www.pnas.org/content/82/5/1563.full.pdf

Is Paeonol an effective MAO inhibitor?

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.

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?

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.

Summary

• Paeonol is a constituent of various types of TCM and has been recently released as a Monoamine Oxidase Inhibitor
• Studies show that the concentration necessary to inhibit MAO-A and MAO-B are 54.6 micromoles and 42.5 micromoles, respectively.
• 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.

References

[1] http://www.sciencedirect.com/science/article/pii/S0378874104000431

[2] http://www.qlhcpi.com/chengguo/lunwen_009.pdf

Future Pharmacy III: Nobiletin

Introduction
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.

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Methoxyoctopamine: Structure & Activity

p-Methoxyoctopamine (Para-Methoxy-Octopamine, P-OMe-Octopamine) is an interesting compound formed after en vivo hydrolysis of various natural amides such as Aegeline and Tembamide.

Structure Activity Relationships (SAR)

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.

Beta-Agonism 

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 already deactivated. Conversely, a para-methoxy substituent does not 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.

CNS Stimulation

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 in the absence of the beta-OH. 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). 

Releasing

Since methoxyoctopamine is a primary phenylethylamine, it may still retain properties related to catecholamine releasement (See the Pharmacology of 1,3-DMAA). 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.

Summary

• Para-Methoxy-Octopamine formed after en vivo hydrolysis of Aegeline and Tembamide.
• The para-methoxy substituent removes beta-1 and beta-2 adrenergic receptor affinity, although still allowing for the possibility of beta-3 receptor affinity.
• No ability to induce lipolysis (fat loss) in humans
• The beta-OH removes substantial CNS penetration.
• No ability to produce CNS stimulation.
• May still retain catecholamine releasing potential, allowing for transient peripheral stimulation.
• Much better alternatives exist.

New "Anabolic:" Aegeline

Introduction
Aegeline (N-[2-hydroxy-2(4-methoxyphenyl) ethyl]-3-phenyl-2-propenamide) 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.

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.

Pharmacology
In the murine model of diabetes, 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 murine model of dyslipdemia (1). The authors concluded, "The reasonable mapping of [aegeline] to validated pharmacophoric hypothesis and 3D QSAR model with an estimated activity (283 nM) suggest that [aegeline] might be a beta(3)-AR agonist." A follow-up study done in 2011 by the same researchers confirmed aegelines antihyperlipidemic & antihyperglycemic properties (2). 

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). 


Summary
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. 

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.


References
(1) http://www.ncbi.nlm.nih.gov/pubmed/17197179
(2) http://www.ncbi.nlm.nih.gov/pubmed/21930379
(3) http://jpet.aspetjournals.org/content/299/1/96.long
(4) http://link.springer.com/article/10.1007%2FPL00005357?LI=true
(5) http://www.ncbi.nlm.nih.gov/pubmed/8121236