Phenethylamine

Substituted derivatives

Substituted phenethylamines are a chemical class of organic compounds based upon the phenethylamine structure;^{[note 2]} the class is composed of all the derivative compounds of phenethylamine which can be formed by replacing, or substituting, one or more hydrogen atoms in the phenethylamine core structure with substituents.

Many substituted phenethylamines are psychoactive drugs, which belong to a variety of different drug classes, including central nervous system stimulants (e.g., amphetamine), hallucinogens (e.g., 2,5-dimethoxy-4-methylamphetamine), entactogens (e.g., 3,4-methylenedioxyamphetamine), appetite suppressants (e.g. phentermine), nasal decongestants and bronchodilators (e.g., pseudoephedrine), antidepressants (e.g. bupropion), antiparkinson agents (e.g., selegiline), and vasopressors (e.g., ephedrine), among others. Many of these psychoactive compounds exert their pharmacological effects primarily by modulating monoamine neurotransmitter systems; however, there is no mechanism of action or biological target that is common to all members of this subclass.

Numerous endogenous compounds—including hormones, monoamine neurotransmitters, and many trace amines (e.g., dopamine, norepinephrine, adrenaline, tyramine, and others)—are substituted phenethylamines. Dopamine is simply phenethylamine with a hydroxyl group attached to the 3 and 4 position of the benzene ring. Several notable recreational drugs, such as MDMA (ecstasy), methamphetamine, and cathinones, are also members of the class. All of the substituted amphetamines are phenethylamines, as well.

Pharmaceutical drugs that are substituted phenethylamines include phenelzine, phenformin, and fanetizole, among many others.

The N-methylated derivative of phenethylamine is N-methylphenethylamine.

Analogues

Analogues of phenethylamine with the ethylamine side chain extended or shortened include phenylpropylamine and benzylamine. Another related analogue is phenylalaninol.

Synthesis

One method for preparing β-phenethylamine, set forth in J. C. Robinson and H. R. Snyder's Organic Syntheses (published 1955), involves the reduction of benzyl cyanide with hydrogen in liquid ammonia, in the presence of a Raney-Nickel catalyst, at a temperature of 130 °C and a pressure of 13.8 MPa. Alternative syntheses are outlined in the footnotes to this preparation.^[22]

A much more convenient method for the synthesis of β-phenethylamine is the reduction of ω-nitrostyrene by lithium aluminium hydride in ether, whose successful execution was first reported by R. F. Nystrom and W. G. Brown in 1948.^[23]

Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.^[24]

Assembling phenethylamine structures for synthesis of compounds such as epinephrine, amphetamines, tyrosine, and dopamine by adding the beta-aminoethyl side chain to the phenyl ring is possible. This can be done via Friedel-Crafts acylation with N-protected acyl chlorides when the arene is activated, or by Heck reaction of the phenyl with N-vinyloxazolone, followed by hydrogenation, or by cross-coupling with beta-amino organozinc reagents, or reacting a brominated arene with beta-aminoethyl organolithium reagents, or by Suzuki cross-coupling.^[25]

Detection in body fluids

This section needs expansion with: [5]. You can help by adding to it. (September 2016)

Reviews that cover attention deficit hyperactivity disorder (ADHD) and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine concentrations in ADHD individuals when compared with controls.^[26] In treatment-responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine concentration.^[26] An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.^[26]

Thirty minutes of moderate- to high-intensity physical exercise has been shown to induce an increase in urinary phenylacetic acid, the primary metabolite of phenethylamine.^[3][27][28] Two reviews noted a study where the mean 24 hour urinary phenylacetic acid concentration following just 30 minutes of intense exercise rose 77% above its base level;^[3][27][28] the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30 seconds.^{[3][27][28][4]} In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate as dopamine is produced.^[4] Monoamine oxidase deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone. Similarly, β-PEA would not be completely deaminated in the gut as it is a selective substrate for MAO-B, which is not primarily 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.^[14] 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. Because of the pharmacological relationship between phenethylamine and amphetamine, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both phenethylamine and amphetamine are potent euphoriants.^[3][27][28]

Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.^[10][29]

Monoamine releasing agent

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, is a releasing agent of norepinephrine and dopamine.^[11][12][42] It is roughly equipotent to amphetamine in this regard in vitro.^[32] Phenethylamine is inactive as a psychostimulant under normal circumstances due to rapid metabolism by monoamine oxidase (MAO), but can become active in the presence of a monoamine oxidase inhibitor (MAOI).^[32]

TAAR1 agonist

Phenethylamine is a potent agonist of the mouse, rat, and human trace amine-associated receptor 1 (TAAR1).^[43][2] β-PEA is also an odorant binding TAAR4 in mice thought to mediate predator avoidance.^[44] Similarly to the case of amphetamine, phenethylamine shows enhanced locomotor stimulation, a psychostimulant-like effect, in TAAR1 knockout mice.^[45]

Monoaminergic activity enhancer

Phenethylamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its catecholamine-releasing activity.^[46][47][48] That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.^[46][47][48] The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines.^[46][47][48] The MAE actions of phenethylamine and other MAEs may be mediated by TAAR1 agonism.^[49][50] Synthetic and more potent MAEs like phenylpropylaminopentane (PPAP) and selegiline (L-deprenyl) have been derived from phenethylamine.^[46][47]

Other activities

Unlike its derivatives norepinephrine (noradrenaline) and epinephrine (adrenaline), phenethylamine is inactive as an agonist of the α- and β-adrenergic receptors.^[51]

Effects in animals and humans

According to Alexander Shulgin in PiHKAL, phenethylamine is completely inactive in humans at doses of up to 1,600 mg orally and 50 mg intravenously.^[52] This can be attributed to its extremely rapid metabolic breakdown rather than pharmacodynamic inactivity.^[52]

Although exogenous phenethylamine on its own is inactive, its metabolism can be strongly inhibited and it can thereby become active, showing psychostimulant effects, when combined with a monoamine oxidase inhibitor (MAOI), specifically monoamine oxidase B (MAO-B) inhibitors like selegiline.^[53][54] Oral L-phenylalanine (a precursor of phenethylamine) and/or phenethylamine itself in combination with selegiline has been studied in the treatment of depression and has been reported to be effective.^{[46][55][56][57][58]} Misuse of phenethylamine in combination with selegiline has also been reported.^[59][60]

The LD₅₀Tooltip median lethal dose values of phenethylamine include 175 mg/kg i.p. in mice, 320 mg/kg s.c. in mice, 100 mg/kg i.v. in mice, 100 mg/kg parenterally in mice, 39 mg/kg intracervically in mice, and 200 mg/kg i.p. in guinea pigs.^[10] Its LD_Lo values include 800 mg/kg p.o. in rats, 100 mg/kg i.p. in rats, 450 μg/kg s.c. in rats, and 300 mg/kg via an unspecified route in mice.^[10]