Saturday, January 19, 2013

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.

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). 

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.

  • 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.

Tuesday, January 8, 2013

New "Anabolic:" Aegeline

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.

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). 

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.