N-Methylphenethylamine

Not to be confused with amphetamine or β-Methylphenethylamine.

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA).^[2][3] It has been detected in human urine (<1 μg over 24 hours)^[4] and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects.^[2][3] PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to remain present and produce psychoactive effects.

N-Methylphenethylamine^[1]

Names
Preferred IUPAC name N-Methyl-2-phenylethan-1-amine
Other names N-Methyl-2-phenylethanamine N-Methylphenethylamine N-Methyl-β-phenethylamine [citation needed]
Identifiers
CAS Number	589-08-2 Y
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL45763 Y
ChemSpider	11019 Y
ECHA InfoCard	100.008.758
PubChem CID	11503
UNII	02N4V81704 Y
CompTox Dashboard (EPA)	DTXSID10207629
InChI InChI=1S/C9H13N/c1-10-8-7-9-5-3-2-4-6-9/h2-6,10H,7-8H2,1H3 Y Key: SASNBVQSOZSTPD-UHFFFAOYSA-N Y InChI=1/C9H13N/c1-10-8-7-9-5-3-2-4-6-9/h2-6,10H,7-8H2,1H3 Key: SASNBVQSOZSTPD-UHFFFAOYAA
SMILES CNCCc1ccccc1
Properties
Chemical formula	C9H13N
Molar mass	135.210 g·mol−1
Appearance	Colorless liquid
Density	0.93 g/mL
Boiling point	203 °C (397 °F; 476 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

PEA and NMPEA are both alkaloids that are found in a number of different plant species as well.^[5] Some Acacia species, such as A. rigidula, contain remarkably high levels of NMPEA (~2300–5300 ppm).^[6] NMPEA is also present at low concentrations (< 10 ppm) in a wide range of foodstuffs.^[7]

NMPEA is a positional isomer of amphetamine.^[8]

Biosynthesis

Biosynthetic pathways for catecholamines and trace amines in the human brain[9][10][11] L-Phenylalanine L-Tyrosine L-DOPA Epinephrine Phenethylamine p-Tyramine Dopamine Norepinephrine N-Methylphenethylamine N-Methyltyramine p-Octopamine Synephrine 3-Methoxytyramine AADC AADC AADC primary pathway PNMT PNMT PNMT PNMT AAAH AAAH brain CYP2D6 minor pathway COMT DBH DBH N-methylphenethylamine, an endogenous compound in humans,[3] is an isomer of amphetamine with the same biomolecular target, TAAR1, a G protein-coupled receptor which modulates catecholamine neurotransmission.[12]

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^[13]). It forms a hydrochloride salt, m.p. 162–164 °C.^[14]

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.^[13] 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 – labeled methyl iodide), and then the amide hydrolyzed.^[15]

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.^[16]

Pharmacology

NMPEA is a pressor, with 1/350 x the potency of epinephrine.^[17]

Like its parent compound, PEA, and isomer, amphetamine, NMPEA is a potent agonist of human trace amine-associated receptor 1 (hTAAR1).^[3][18] It has comparable pharmacodynamic and toxicodynamic properties to that of phenethylamine, amphetamine, and other methylphenethylamines in rats.^[8]

As with PEA, NMPEA is metabolized relatively rapidly by monoamine oxidases during first pass metabolism;^[3][18] both compounds are preferentially metabolized by MAO-B.^[3][18]

Toxicology

The "minimum lethal dose" (mouse, i.p.) of the HCl salt of NMPEA is 203 mg/kg;^[19] the LD₅₀ for oral administration to mice of the same salt is 685 mg/kg.^[20]

Acute toxicity studies on NMPEA show an LD₅₀ = 90 mg/kg, after intravenous administration to mice.^[21]