N-Methylphenethylamine

N-Methylphenethylamine (NMPEA), a positional isomer of amphetamine, is a naturally occurring trace amine neurotransmitter in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected (< 1 μg/24 hrs.) in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate. PEA and NMPEA are both alkaloids that are found in a number of different plant species as well. Some Acacia species, such as A. rigidula, contain remarkably high levels of NMPEA (~2300â€"5300 ppm). NMPEA is also present at low concentrations (< 10 ppm) in a wide range of foodstuffs.

Chemistry

In appearance, NMPEA is a colorless liquid. NMPEA is a weak base, with pK_a = 10.14; pK_b = 3.86 (calculated from data given as K_b). It forms a hydrochloride salt, m.p. 162â€"164°C.

Although NMPEA is available commercially, it may be synthesized by various methods. An early synthesis reported by Carothers and co-workers involved conversion of phenethylamine to its p-toluenesulfonamide, followed by N-methylation using methyl iodide, then hydrolysis of the sulfonamide. A more recent method, similar in principle, and used for making NMPEA radio-labeled with ¹⁴C in the N-methyl group, started with the conversion of phenethylamine to its trifluoroacetamide. This was N-methylated (in this particular case using ¹⁴C â€" labeled methyl iodide), and then the amide hydrolyzed.

NMPEA is a substrate for both MAO-A (K_M = 58.8 μM) and MAO-B (K_M = 4.13 μM) from rat brain mitochondria.

Pharmacology

NMPEA is a pressor, with 1/350 x the potency of epinephrine.

Like its parent compound, PEA, and isomer, amphetamine, NMPEA is a potent agonist of human TAAR1. It has comparable pharmacodynamic and toxicodynamic properties to that of phenethylamine, amphetamine, and other methylphenethylamines in rats.

As with PEA, NMPEA is metabolized relatively rapidly by monoamine oxidases during first pass metabolism; both compounds are preferentially metabolized by MAO-B.

Toxicology

The "minimum lethal dose" (mouse, i.p.) of the HCl salt of NMPEA is 203 mg/kg; the LD₅₀ for oral administration to mice of the same salt is 685 mg/kg.

Acute toxicity studies on NMPEA show an LD₅₀ = 90 mg/kg, after intravenous administration to mice.

References