Wednesday, December 14, 2011

Pharmacology of N-Coumaroyldopamine

N-coumaroyldopamine is a novel phenylpropenic acid derivative extracted from Theobroma cacao 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.

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.

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.

Conversely, dobutamine will not undergo hydrolysis at its amine, and is therefore actually more metabolically stable then N-coumaroyldopamine. Even so, dobutamines half-life is only 2 minutes due to the metabolic processes described above.

Dopamine Prodrug
As mentioned above, another of N-Coumaroyldopamine's metabolic pathways involves hydrolysis of its amide bond.

Due to the ubiquity of biological hydrolases, the main metabolites of N-Coumaroyldopamine will be Dopamine and a cinnamic acid analogue.

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).

N-Coumaroyldopamine is a highly selective beta2 agonist only in its unmetabolized 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.

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.

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.

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.


Pharmacology of Halostachine

Halostachine (N-methylphenylethanolamine) is a very mild sympathomimetic agent with partial adrenergic binding potential (1).

Figure 1: Halostachine demonstrating partial agonism on the beta-2 adrenergic receptor. ISO - Isoproterenol, EPI - Epinephrine, NE - Norepinephrine, DOP - Dopamine, SAL - Salbutamol, HAL - Halostachine. (7)

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).

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).

Halostachine is rapidly metabolized by MAO and has a half-life of approximately 5-10 minutes (2, 5).

Structure Activity and Summary:
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.

“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)”

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.