N-Methyltyramine (NMT), also known as 4-hydroxy-N-methylphenethylamine, is a human trace amine and natural phenethylamine alkaloid found in a variety of plants. As the name implies, it is the N-methyl analog of tyramine, which is a well-known biogenic trace amine with which NMT shares many pharmacological properties. Biosynthetically, NMT is produced by the N-methylation 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 for the first time, from germinating barley 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. Since barley, via its conversion to malt, is used extensively in the production of beer, 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. 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. NMT is found in bitter orange, 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. 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 at 250 °C. Although N-methyltyrosine occurs naturally, it was made by the methylation of tyrosine using dimethyl sulfate. NMT was also made by Kirkwood and Marion starting from 4-methoxyphenethylamine, but this was first converted to the imine with benzaldehyde, followed by methylation with dimethyl sulfate; 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).
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