''N''-Methylphenethylamine (NMPEA) is a

naturally occurring 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 sy ...

trace amine neuromodulator in humans that is derived from the trace amine,

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 ...

(PEA). It has been detected in human urine (<1 μg over 24 hours) and is produced by

phenylethanolamine N-methyltransferase Phenylethanolamine ''N''-methyltransferase (PNMT) is an enzyme found primarily in the adrenal medulla that converts norepinephrine (noradrenaline) to epinephrine (adrenaline). It is also expressed in small groups of neurons in the human brain and ...

with

as a substrate. PEA and NMPEA are both

alkaloids 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 st ...

that are found in a number of different plant species as well. Some ''

Acacia ''Acacia'', commonly known as the wattles or acacias, is a large genus of shrubs and trees in the subfamily Mimosoideae of the pea family Fabaceae. Initially, it comprised a group of plant species native to Africa and Australasia. The genus na ...

'' species, such as '' A. rigidula'', contain remarkably high levels of NMPEA (~2300–5300 ppm). NMPEA is also present at low concentrations (< 10 ppm) in a wide range of foodstuffs. NMPEA is a

positional isomer In chemistry, a structural isomer (or constitutional isomer in the IUPAC nomenclature) of a compound is another compound whose molecule has the same number of atoms of each element, but with logically distinct bonds between them. The term meta ...

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

Biosynthesis

Chemistry

In appearance, NMPEA is a colorless liquid. NMPEA is a

weak base A weak base is a base that, upon dissolution in water, does not dissociate completely, so that the resulting aqueous solution contains only a small proportion of hydroxide ions and the concerned basic radical, and a large proportion of undissociat ...

, with pK_a = 10.14; pK_b = 3.86 (calculated from data given as K_bW.H. Carothers, C. F. Bickford and G. J. Hurwitz (1927) ''J. Am. Chem. Soc.'' 49 2908–2914.). It forms a hydrochloride salt, m.p. 162–164°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 Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one h ...

, 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 – labeled methyl iodide), and then the amide hydrolyzed. NMPEA is a substrate for both

MAO-A Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, s ...

(K_M = 58.8 μM) and

MAO-B Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. ...

(K_M = 4.13 μM) from rat brain mitochondria.

Pharmacology

NMPEA 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 1/350 x the potency of

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 ...

. Like its parent compound, PEA, and isomer,

, NMPEA is a potent

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 ...

human trace amine-associated receptor 1 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 ...

(hTAAR1). It has comparable

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for ...

and toxicodynamic properties to that of phenethylamine, amphetamine, and other

methylphenethylamine Methylphenethylamine may refer to: * α-Methylphenethylamine (amphetamine) * β-Methylphenethylamine * ''N''-Methylphenethylamine (an endogenous trace amine in humans) * 2-Methylphenethylamine * 3-Methylphenethylamine * 4-Methylphenethylamine ...

s in rats. As with PEA, NMPEA is metabolized relatively rapidly by

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...

s during

first pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...

; both compounds are preferentially metabolized by

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.A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." ''J. Pharmacol. Exp. Ther.'' 106 341–345.

References

{{DEFAULTSORT:Methylphenethylamine, N- Phenethylamine alkaloids TAAR1 agonists Amphetamine Trace amines Phenethylamines Norepinephrine-dopamine releasing agents Amino acid derivatives Secondary amines