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

Future Pharmacy II

The Future of Stimulants
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 (See this formula: 400 mg of caffeine per serving!). Others have resorted to using non-DSHEA approved stimulants like N-Isopropyloctopamine (See this formula). Still others are relying upon gimmicks like "Acacia Rigidula 98%" extracts (See Shulgin's thoughts on Acacia, and this recent study).

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 this study).

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.

Conessine
This is a natural plant extract of Holarrhena antidysenterica 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).

H3 antagonists have been studied for the past few decades for treating narcolepsy and ADHD since they are centrally stimulating (Read more here). 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).

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 without peripheral effects 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.

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.


Summary

• The Federal Analog Act (FAA) limits the utility of using the phenylethylamine backbone for new or novel stimulants found in nature.
• H3 antagonism is a novel method to induce stimulation that largely circumvents the FAA
• 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.

References
(1) http://www.ncbi.nlm.nih.gov/pubmed/18554904
(2) http://www.ncbi.nlm.nih.gov/pubmed/22356925
(3) http://www.ncbi.nlm.nih.gov/pubmed/18683917