PEA and NMPEA are bothalkaloids that are found in a number of different plant species as well.[4] SomeAcacia species, such asA. rigidula, contain remarkably high levels of NMPEA (~2300–5300 ppm).[5] NMPEA is also present at low concentrations (< 10 ppm) in a wide range of foodstuffs.[6]
In appearance, NMPEA is a colorless liquid. NMPEA is aweak base, with pKa = 10.14; pKb = 3.86 (calculated from data given as Kb[12]). It forms a hydrochloride salt, m.p. 162–164 °C.[13]
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 itsp-toluenesulfonamide, followed byN-methylation usingmethyl iodide, then hydrolysis of the sulfonamide.[12] A more recent method, similar in principle, and used for making NMPEA radio-labeled with14C in the N-methyl group, started with the conversion of phenethylamine to its trifluoroacetamide. This was N-methylated (in this particular case using14C – labeled methyl iodide), and then the amide hydrolyzed.[14]
NMPEA is a substrate for bothMAO-A (KM = 58.8 μM) andMAO-B (KM = 4.13 μM) from rat brain mitochondria.[15]
The "minimum lethal dose" (mouse, i.p.) of the HCl salt of NMPEA is 203 mg/kg;[18] the LD50 for oral administration to mice of the same salt is 685 mg/kg.[19]
Acute toxicity studies on NMPEA show an LD50 = 90 mg/kg, after intravenous administration to mice.[20]
^abPendleton RG, Gessner G, Sawyer J (September 1980). "Studies on lung N-methyltransferases, a pharmacological approach".Naunyn-Schmiedeberg's Arch. Pharmacol.313 (3):263–8.doi:10.1007/bf00505743.PMID7432557.S2CID1015819.
^abcdefBroadley KJ (March 2010). "The vascular effects of trace amines and amphetamines".Pharmacol. Ther.125 (3):363–375.doi:10.1016/j.pharmthera.2009.11.005.PMID19948186.Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ... Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ... Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ... Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
^G. P. Reynolds and D. O. Gray (1978)J. Chrom. B: Biomedical Applications145 137–140.
^T. A. Smith (1977). "Phenethylamine and related compounds in plants."Phytochemistry16 9–18.
^B. A. Clement, C. M. Goff and T. D. A. Forbes (1998)Phytochemistry49 1377–1380.
^G. B. Neurath et al. (1977)Fd. Cosmet. Toxicol.15 275–282.
^abMosnaim AD, Callaghan OH, Hudzik T, Wolf ME (April 2013). "Rat brain-uptake index for phenylethylamine and various monomethylated derivatives".Neurochem. Res.38 (4):842–6.doi:10.1007/s11064-013-0988-1.PMID23389662.S2CID18514146.
^Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family".Trends in Pharmacological Sciences.26 (5):274–281.doi:10.1016/j.tips.2005.03.007.PMID15860375.
^Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D".European Journal of Pharmacology.724:211–218.doi:10.1016/j.ejphar.2013.12.025.PMID24374199.
^abcLindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family".Trends Pharmacol. Sci.26 (5):274–281.doi:10.1016/j.tips.2005.03.007.PMID15860375.In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors.
^A. M. Hjort (1934)J. Pharm. Exp. Ther.52 101–112.
^C. M. Suter and A. W. Weston (1941)J. Am. Chem. Soc.63 602–605.
^A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives."J. Pharmacol. Exp. Ther.106 341–345.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
