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.


Wednesday, November 30, 2011

Top 8 Worst Stimulants of All Time

1. Halostachine

2. N-Methyltyramine

3. Tyramine
  • Pros: None
  • Cons: 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

4. Para-Synephrine ("Synephrine")

5. 3,3'-Diiodo-L-Thyronine

6. 3,5-Diiodo-L-Thyronine
  • Pros: Can help manage hyperthyroidism
  • Cons: 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
  • References:
  • (1) 
  • (2) 3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro. Journal of Molecular Endocrinolog (1997) 19, 137-147

7. Hordenine
  • Pros: Weak competitive inhibition of MAO-B
  • Cons: Minimal bioavailability; Elimination half-life of 20-30 minutes; No CNS penetration

8. Phenylethylamine
  • Pros: Transient high
  • Cons: Rapidly metabolised (Half-life of 5-10 minutes); No direct receptor agonism; Sympatholytic with chronic supplementation; Competitive inhibitor of beta-hydroxylase

Wednesday, June 29, 2011

Pharmacology of p-Synephrine

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.

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).

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.

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.

Structure and Activity
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.

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.

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).

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).

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.

Vesicular Exchange-Diffusion
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.

p-Synephrine and Fat Loss
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.

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.

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.

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.

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.

p-Synephrine sources (Synthetic)
1. Primaforce
2. SNS


Sunday, June 26, 2011

Pharmacology of 1,3-Dimethylamylamine

1,3-Dimethylamylamine (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.

Structure Activity Relationships

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 Reuptake Inhibition below). Furthermore, an alpha methyl substituent increases the compounds amphipathism which expedites CNS penetration.

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.

Catecholamine Releasing Properties

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.

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.

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.

Reuptake Inhibition
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.

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).

Another structural alteration which decreases 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).

DMAA and Human Physiology
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.

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.

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.

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.

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 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.

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.


Monday, June 20, 2011

New Stimulant: N-MethylTyramine

Compound: N-MethylTyramine (4-Hydroxy-N-methylphenethylamine)
Source: Citrus aurantium
CAS: 370-98-9
Half-life: 5.6 min

N-MethylTyramine (NMT) 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.

Primary metabolic reactions

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.

Structure Activity Relationship

A: 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.

B1;B2: 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).

C: 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. 

D: 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.

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.

Acute 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.