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

Pharmacology of N-Acetyl-L-Tyrosine

Introduction
N-Acetyl-L-Tyrosine (N-Acetyl-Tyrosine, N-acetyltyrosine, NAT) is a novel aromatic amino acid derivative commonly found in pre-workout drinks or other ergogenic sports supplements. This compound is purported to increase the bioavailability of L-Tyrosine. It may also be formed intrahepatically by the enzyme N-acetyltransferase as a mechanism of disposing aromatic amino acids (L-Phenylalanine, L-Tyrosine, L-Dopa).

Characteristics
N-Acetyl-Tyrosine has a water solubility of 2.3 mg/ml, whereas L-Tyrosine has a water solubility of 0.49 mg/ml. Increasing a compounds water solubility is a method that may enhance bioavailability, especially if the compound is particularly insoluble. Conversely, increasing water solubility may actually negatively impact its kinetics by shortening its half-life through urinary excretion. In the case of L-tyrosine, although it has limited water solubility, it has been shown to have adequate bioavailability. In humans, doses as low as 100 mg have been shown to elevate plasma tyrosine levels for as long as 7 hours (1). Doses as high as 7 grams have produced plasma tyrosine levels 223% above baseline (2). As we will see in the next section, doses of N-Acetyl-Tyrosine as high as 5 grams have only shown an elevation of tyrosine of 25% from baseline.

Pharmacokinetics
Since NAT does not possess intrinsic pharmacological properties, the most important question is: Does this compound actually become L-tyrosine? The answer is yes, albeit inefficiently. The enzymes Aminoacylase I-III are primarily located in the kidneys and are responsible for removing the acetyl group from the tyrosine molecule (3). In 1985, a proof-of-concept rodent study was designed to determine the utility of replacing the much less soluble tyrosine, with the much more soluble NAT, for total parenteral nutrition (4). They found that, at a dose of 0.5 mmol/kg body weight, NAT infusion was "not sufficient to increase plasma tyrosine concentrations above fasting levels." Converting this dose to a Human Equivalent Dose (HED) times Body Surface Area (BSA) equals a dose of about 1.25 grams. Furthermore, the study also confirmed the inefficiency of N-acetyl removal by measuring the amount of unchanged compound in the urine. With radioactive carbon tracing, they found that 74% of the supplemented form was lost in the urine as unchanged NAT, and only 23% was lost as tyrosine. This amounts to a very inefficient intrarenal conversion rate of about 25%.

Two years later, the study was repeated in humans, although using much higher levels of NAT (5). In this study they compared the usefulness of N-Acetyl-Tyrosine as a more soluble amino acid precursor by infusing these compounds as an IV bolus (5 grams), or as a 4 hour IV infusion. Similar to the rodent study, they found that the NAT infusion only yielded meager increases in plasma tyrosine (up to 25% from baseline), and that the majority (56%) of NAT was excreted unchanged into the urine. The authors commented: "We conclude that under these conditions the usefulness of NAT ... as precursors for the corresponding amino acids in humans is not apparent."

Blood Brain Barrier (BBB)
One of the most discussed uses for N-Acetyl-Tyrosine on the internet concerns the elevation brain tyrosine levels. The idea is that NAT, being a precursor to L-Tyrosine, would allow for greater BBB penetration as a function of direct penetration, or by increasing plasma tyrosine pools through stepwise conversion into L-tyrosine via N-deacetylation, and therefore could be useful in increasing mood, or as a general nootropic. Unfortunately, as the former sections discuss, NAT is a very inefficient tyrosine pro-drug. With regards to the former, a 1989 study analyzed the ability of 3 different compounds in elevating central tyrosine levels when compared to tyrosine itself (6). Both O-phospho-L-tyrosine and L-tyrosine methyl ester were successfully bioequivalent to tyrosine, whereas N-Acetyl-Tyrosine was ineffective.

Summary

• Inefficient pro-drug to L-tyrosine
• The majority of N-Acetyl-L-Tyrosine is excreted as unchanged compound
• Doses as high as 5 grams in humans have only produced meager elevations in plasma tyrosine
• No BBB penetration
• Much greater water solubility; unknown significance

References
(1) http://www.journalogy.net/Publication/11933288/l-tyrosine-ameliorates-some-effects-of-lower-body-negative-pressure-stress
(2) http://www.journalogy.net/Publication/30276820/randomised-controlled-trial-of-tyrosine-supplementation-on-neuropsychological-performance-in
(3) http://www.sciencedirect.com/science/article/pii/0005274478900232
(4) http://www.nature.com/pr/journal/v19/n6/abs/pr19851993a.html
(5) http://www.sciencedirect.com/science/article/pii/002604958990005X
(6) http://onlinelibrary.wiley.com/doi/10.1111/j.2042-7158.1989.tb06368.x/abstract

Pharmacology of N-Methyl-Tyrosine

Introduction
N-Methyl-Tyrosine (NMTyr), also known as Surinamine, is an amino acid found in the Andira & Rhatany species of plant. This compound was recently released in a stimulant pre-workout formula as a component of the "Shred complex (1)." Ironically, N-Methyl-Tyrosine was investigated in the 1940's as an anti-stimulant.

Pharmacokinetics
As the name suggests, N-Methyl-Tyrosine is the N-methylated analogue of L-Tyrosine. Differing from L-Tyrosine in its pharmacokinetics however, NMTyr is unable to become hydroxylated on the meta position of the benzyl ring. This conversion would normally convert L-Tyrosine into L-Dopa via the enzyme Tyrosine Hydroxylase. In fact, N-Methyl-Tyrosine is still offered from various laboratories as a tyrosine hydroxylase inhibitor (2).

Without the ability to become a true catchol, the next step would normally be decarboxylation. Unfortunately, NMTyr is not a substrate for dopa decarboxylase, and therefore is a metabolic dead-end (3).

The production of CO2 is an indicator of decarboxylase activity. N-methyl-tyrosine is unreactive.

Pharmacodynamics
N-Methyl-Tyrosine possesses a carboxylic acid on the alpha carbon which prevents direct adrenergic receptor binding, in addition to deamination throught steric hindrance. The former modality creates a physiologic receptor antagonist via the law of mass action and vesicular depletion, and the latter increases its half-life, extending its enzymatic inhibition for a longer period of time. Even in the unlikely event of decarboxylation, NMTyr would simply yield non-beta-hydroxylated, para-hydroxylated, metabolites including NMT, which would only excacerbate its anti-adrenergic potential.

Summary

• Anti-Stimulant
• Inhibits Tyrosine hydroxylase - Decreases the natural production of catecholamines/neurotransmitters
• Not a substrate for Dopa decarboxylase - No potential for metabolic improvement
• Competes for neuronal vesicular uptake with viable precursors (L-tyrosine, L-dopa, L-Phenylalanine) - Physiologic competitive antagonist

References
(1) http://directnutrition.com.au/media/wysiwyg/Albuterex_-_Nutritional_Info.jpg
(2) http://www.chemicalbook.com/ChemicalProductProperty_DE_CB2212948.htm
(3) http://jp.physoc.org/content/101/3/337.full.pdf