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''N''-Methyltyramine (NMT), also known as 4-hydroxy-''N''-methylphenethylamine, is a human
trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the ...
and natural
phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
found in a variety of plants.T. A. Smith (1977). "Phenethylamine and related compounds in plants." ''Phytochemistry'' 16 9 – 18. As the name implies, it is the N-methyl analog of
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
, which is a well-known
biogenic A biogenic substance is a product made by or of life forms. While the term originally was specific to metabolite compounds that had toxic effects on other organisms, it has developed to encompass any constituents, secretions, and metabolites of p ...
trace amine with which NMT shares many pharmacological properties. Biosynthetically, NMT is produced by the N-
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of tyramine via the action of the enzyme phenylethanolamine ''N''-methyltransferase in humans and tyramine ''N''-methyltransferase in plants.


Occurrence

N-methyltyramine seems to be quite widely distributed in plants. NMT was isolated as a
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
for the first time, from germinating
barley Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley pr ...
roots, by Kirkwood and Marion in 1950. These chemists found that 600 g of barley, after germination and 10-day growth, yielded 168 mg of N-methyltyramine.S. Kirkwood and L. Marion (1950) ''J. Am. Chem. Soc.'' 72 2522-2524. Since barley, via its conversion to
malt Malt is germinated cereal grain that has been dried in a process known as " malting". The grain is made to germinate by soaking in water and is then halted from germinating further by drying with hot air. Malted grain is used to make beer, wh ...
, is used extensively in the production of
beer Beer is one of the oldest and the most widely consumed type of alcoholic drink in the world, and the third most popular drink overall after water and tea. It is produced by the brewing and fermentation of starches, mainly derived from ce ...
, beer and malt have been examined by several groups of investigators for the presence of NMT. Citing a 1965 study by McFarlane, Poocharoen reported that beer contained ~ 5–8 mg/L of NMT.B. Poocharoen (1983), Ph. D. Thesis, Oregon State University. http://ir.library.oregonstate.edu/xmlui/handle/1957/27227 The NMT content of various malts and malt fractions was extensively studied by Poocharoen himself, who also provided a good coverage of related literature up to 1983. This researcher found a mean concentration of NMT in raw barley of ~ 5 μg/g; in green malts (i.e. barley that had been soaked in water for 2 days then germinated for 4 days), the mean concentration was ~ 21 μg/g, and in kilned malts (i.e. green malts that had been heated in a kiln for 1–2 days) the mean concentration was ~ 27 μg/g. When only green malt roots were examined, their mean content of NMT was ~ 1530 μg/g, whereas the mean level in kilned malt roots was ~ 1960 μg/g. Studies of ''Acacia'' species have shown the presence of significant levels of NMT in their leaves: ~ 240-1240 ppm (or μg/g) in ''A. rigidula'' and ~ 190-750 ppm in ''A. berlandieri''. The seeds of ''A. schweinfurthii'' yielded 440 μg/g of NMT.C. S. Evans, E. A. Bell and E. S. Johnson (1979) ''Phytochemistry'' 18 2022-2023. NMT is found in
bitter orange Bitter orange, Seville orange, bigarade orange, or marmalade orange is the citrus tree ''Citrus'' × ''aurantium'' and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of the world. It is probably a cross bet ...
, ''Citrus aurantium'', and a concentration of ~ 180 μg/g has been reported from an extract made from the ripe fruit, although the method by which this extract was prepared is not very clearly described.


Chemistry


Synthesis

NMT has been synthesized in a number of ways. One of the earliest syntheses is that reported by Walpole, who made it by the following sequence of steps: (i) acetylation of 4-methoxyphenethylamine with acetic anhydride; (ii) methylation of the amide using Na/methyl iodide; (iii) cleavage of the methyl ether to the phenol using HI; (iv) hydrolysis of the N-acetyl group with aqueous HCl. Walpole also described an alternative, but similar sequence of reactions leading to NMT, beginning with the conversion of 4-methoxyphenethylamine to its benzenesulfonamide, which was then N-methylated and de-protected.G. S. Walpole (1910) ''J. Chem. Soc., Trans.'' 97 941-999. A different method for making NMT was given by Corti, who prepared it by the thermal decarboxylation of N-methyltyrosine (ratanhin), by heating the amino-acid in
fluorene Fluorene , or 9''H''-fluorene is an organic compound with the formula (C6H4)2CH2. It forms white crystals that exhibit a characteristic, aromatic odor similar to that of naphthalene. It has a violet fluorescence, hence its name. For commercial pu ...
at 250 °C. Although N-methyltyrosine occurs naturally, it was made by the methylation of
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
using dimethyl sulfate. NMT was also made by Kirkwood and Marion starting from 4-methoxyphenethylamine, but this was first converted to the
imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
with benzaldehyde, followed by methylation with
dimethyl sulfate Dimethyl sulfate (DMS) is a chemical compound with formula (CH3O)2SO2. As the diester of methanol and sulfuric acid, its formula is often written as ( CH3)2 SO4 or Me2SO4, where CH3 or Me is methyl. Me2SO4 is mainly used as a methylating agent ...
; the product was converted to N-methyl-4-methoxyphenethylamine, and finally de-O-methylated with HBr to give N-methyltyramine.


Common Salts

N-methyltyramine hydrochloride, C9H13NO.HCl: m.p. 148.5 °C; highly soluble in water and in ethanol. N-methyltyramine hydrogen oxalate, C9H13NO.C2H2O4: m.p. 250 °C; very poorly soluble in water.


Basicity

The apparent (see original article for discussion) pKas for protonated N-methyltyramine are 9.76 (phenolic H) and 10.71 (ammonium H).


Pharmacology

NMT is a
pressor An antihypotensive agent, also known as a vasopressor agent or simply vasopressor, or pressor, is any substance, whether endogenous or a medication, that tends to raise low blood pressure. Some antihypotensive drugs act as vasoconstrictors to inc ...
, with a potency of 1/140 ×
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
.W. H. Hartung (1945) ''Ind. Eng. Chem.'' 37 126-137. On the basis of experiments using dogs, Hjort described NMT as a "very good pressor agent": a blood pressure rise of >130 mm and ~ 5 minutes duration was produced by the injection of 1-2.5 μM of solutions of the HCl salt into dogs weighing ~ 10 kg. A pressor response, which was inhibited by pre-treatment with
reserpine Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces m ...
, to the administration of NMT to goats was reported by Camp.B. J. Camp (1970) ''Am. J. Vet. Res.'' 31 755-762. Subcutaneous administration of 10 mg/kg of the HCl salt of NMT to mice enhanced the release of
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
(NE) from the heart by 36% over control, measured after 2 hours. For comparison, the same dose of
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
hydrochloride caused a release of NE of 50% over control in this assay. A qualitatively similar decrease in the NE content of rat heart after treatment with NMT was observed by Camp. Without giving many experimental details, Evans et al. reported that NMT increased blood pressure in rats, inhibited electrically-induced contractions of the guinea-pig ileum, relaxed
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
-stimulated tone of isolated guinea-pig
trachealis The trachealis muscle is a sheet of smooth muscle in the trachea. Structure The trachealis muscle lies posterior to the trachea and anterior to the oesophagus. It bridges the gap between the free ends of C-shaped rings of cartilage at the poster ...
muscle, and increased the rate and contractile force of isolated guinea-pig atrium. The effect on blood pressure was competitively-antagonized by
guanethidine Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such as norepinephrine. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, upta ...
, while the effects on the isolated atrium were inhibited by
desipramine Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...
. Although doses were not given, NMT was described as being equipotent with tyramine on all tissues. It was also noted that the handling of NMT caused
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
headaches in one of the researchers. NMT has been found to be a potent stimulant of
gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gastrin ...
release in the rat, with an ED50 of ~ 10 μg/kg. These researchers used a bio-assay-guided isolation procedure to show that NMT was the constituent of beer that was responsible for producing enhanced gastrin release, which in turn raises
gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...
secretion. For comparative purposes, they also tested tyramine and N,N-dimethyltyramine (
hordenine Hordenine is an alkaloid of the phenethylamine class that occurs naturally in a variety of plants, taking its name from one of the most common, barley (''Hordeum'' species). Chemically, hordenine is the ''N''-methyl derivative (chemistry), derivat ...
) in their assay, finding that 83 nM/kg (corresponding to 12.5 μg/kg of NMT) of each compound enhanced gastrin release by ~ 58% for NMT, ~ 24% for tyramine, and ~ 60% for hordenine. In order to test the indications from earlier studies that, like tyramine itself, NMT produced most of its pharmacological effects by stimulating
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
(NE) release, Koda and co-workers investigated the action of NMT on α2 adrenoceptors, which are involved in the regulation of NE. These researchers found that NMT competed with the binding of sup>3H p-aminoclonidine to α2 receptors from rat brain with an IC50 of ~5.5 x 10−6M. In common with other α2 antagonists, NMT, at i.p. doses of 20 or 100 mg/kg, was also found to inhibit the hypermotility induced in mice by (−)-
scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomiting ...
in a dose-dependent manner. The same doses of NMT in the absence of scopolamine had no significant effects on locomotor activity in mice. Since NMT is one of the constituents of bitter orange, ''
Citrus aurantium Bitter orange, Seville orange, bigarade orange, or marmalade orange is the citrus tree ''Citrus'' × ''aurantium'' and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of the world. It is probably a cross bet ...
'', Mercader and co-workers studied its effects on
lipolysis Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...
, finding that it ''inhibited'' lipolysis in rats. NMT (in common with tyramine) also failed to stimulate lipolysis in human
adipocytes Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
at a concentration of 10 μg/mL (i.e. ~ 66 μM/L); even at ≥ 100 μg/mL, NMT and tyramine induced only 20% of the lipolysis produced by the reference standard drug,
isoprenaline Isoprenaline, or isoproterenol (brand name: Isoprenaline Macure), is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropylam ...
. NMT is a competitive substrate for MAO. It is known to be a stimulator of pancreatic secretions in rats. NMT has been shown to be an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the
TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily exp ...
, similarly to its parent compound
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
. The EC50 of NMT on the human TAAR1 receptor was ~ 2 μM, compared to ~ 1 μM for
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
.


Pharmacokinetics

The pharmacokinetics of NMT have been studied in rabbits and mice using drug that had been
radiolabeled A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tr ...
with
tritium Tritium ( or , ) or hydrogen-3 (symbol T or H) is a rare and radioactive isotope of hydrogen with half-life about 12 years. The nucleus of tritium (t, sometimes called a ''triton'') contains one proton and two neutrons, whereas the nucleus o ...
at C-3 and C-5 on the benzene ring. Plasma concentrations were measured in the rabbits, whereas distribution, metabolism and excretion were determined in the mice. After i.v. administration to rabbits, the α-phase T1/2 was found to be 0.3 minutes, and the β-phase T1/2 was 5.6 minutes. These figures were indicative of a rapid distribution from blood to tissue and a very short plasma half-life. Within 2 minutes of injection, significant levels of radioactivity were detected in all tissues examined, with the highest amounts being in kidney and liver. No detectable radioactivity was left in the plasma after 30 minutes. Some NMT was found in the brains of mice treated with the drug, indicating that a small amount did cross the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. ~ 80% of the administered dose was recovered from the urine of mice within 1 hour.


Toxicology

LD50 of HCl salt of NMT (mouse; i.p.) = 227 mg/kg. Another acute toxicity study of NMT (under the Sterling-Winthrop company code "WIN 5582") found it to have an LD50 = 275 mg/kg, after intravenous administration to mice.A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." ''J. Pharmacol. Exp. Ther.'' 106 341-345.


See also

*
Tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
*
Octopamine Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...
* Epinine *
N-Methylphenethylamine ''N''-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine (<1 μg over 24 hours) and is produced b ...
*
Hordenine Hordenine is an alkaloid of the phenethylamine class that occurs naturally in a variety of plants, taking its name from one of the most common, barley (''Hordeum'' species). Chemically, hordenine is the ''N''-methyl derivative (chemistry), derivat ...
*
Candicine Candicine is a naturally occurring organic compound that is a quaternary ammonium salt with a phenethylamine skeleton. It is the N,N,N-trimethyl derivative of the well-known biogenic amine tyramine, and, being a natural product with a positively c ...


References

{{DEFAULTSORT:Methyltyramine, N- Phenethylamines Alkaloids found in plants TAAR1 agonists Trace amines