Phenethylamine
Phenethylamine 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 amine-associated receptor 1 and inhibiting vesicular monoamine transporter 2 in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.
Phenethylamine is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, in orally ingested phenethylamine, a significant amount is metabolized in the small intestine by monoamine oxidase B and then aldehyde dehydrogenase, which converts it to phenylacetic acid. This means that for significant concentrations to reach the brain, the dosage must be higher than for other methods of administration. Some authors have postulated that phenethylamine plays a role in affection without substantiating these claims with any direct evidence.
Phenethylamines, or more properly, substituted phenethylamines, are the group of phenethylamine derivatives that contain phenethylamine as a "backbone"; in other words, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the phenethylamine core structure with substituents. The class of substituted phenethylamines includes all substituted amphetamines, and substituted methylenedioxyphenethylamines, and contains many drugs which act as empathogens, stimulants, psychedelics, anorectics, bronchodilators, decongestants, and/or antidepressants, among others.
Natural occurrence
Phenethylamine is produced by a wide range of species throughout the plant and animal kingdoms, including humans; it is also produced by certain fungi and bacteria and acts as a potent antimicrobial against certain pathogenic strains of Escherichia coli at sufficient concentrations.Chemistry
Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group. It is a colourless liquid at room temperature that has a fishy odor, and is soluble in water, ethanol and ether. Its density is 0.964 g/ml and its boiling point is 195 °C. Upon exposure to air, it combines with carbon dioxide to form a solid carbonate salt. Phenethylamine is strongly basic, pKb = 4.17, as measured using the HCl salt, and forms a stable crystalline hydrochloride salt with a melting point of 217 °C. Its experimental log P is 1.41.Substituted derivatives
Substituted phenethylamines are a chemical class of organic compounds based upon the phenethylamine structure; 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, hallucinogens, entactogens, appetite suppressants, nasal decongestants and bronchodilators, antidepressants, antiparkinson agents, and vasopressors, 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 compoundsincluding hormones, monoamine neurotransmitters, and many trace amines 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, 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, 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.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.
Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.
File:Benzyl cyanide electrolytic reduction.png|class=skin-invert-image|450px|center|Electrosynthesis of phenethylamine from benzyl cyanide|thumb
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.
Detection in body fluids
Reviews that cover attention deficit hyperactivity disorder and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine concentrations in ADHD individuals when compared with controls. In treatment-responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine concentration. An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.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. 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; 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. In a resting state, phenethylamine is synthesized in catecholamine neurons from -phenylalanine by aromatic amino acid decarboxylase at approximately the same rate as dopamine is produced. 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. 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.
Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.