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Phenethylamine ( PEA) is an organic compound, natural product 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 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine . To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine biosynthesis 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 microorganism 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 (MAO-B) and then aldehyde dehydrogenase (ALDH), which converts it to phenylacetic acid. This means that for significant 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 . The class of substituted phenethylamines includes all substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx), and contains many drugs which act as empathogens, , psychedelic drug, , , , and/or , among others.
Many substituted phenethylamines are psychoactive drugs, which belong to a variety of different drug classes, including central nervous system stimulants (e.g., amphetamine), (e.g., 2,5-dimethoxy-4-methylamphetamine), (e.g., 3,4-methylenedioxyamphetamine), appetite suppressants (e.g. phentermine), nasal decongestants and (e.g., pseudoephedrine), (e.g. bupropion), antiparkinson agents (e.g., selegiline), and (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 compoundsincluding , monoamine neurotransmitters, and many (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 , 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-methyl group derivative of phenethylamine is N-methylphenethylamine.
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.
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 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.
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 L-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 euphoria effects of a runner's high, as both phenethylamine and amphetamine are potent .
Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.
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| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The bioassay were done in rat brain and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: | ||||
Although exogenous phenethylamine on its own is inactive, its metabolism can be strongly inhibited and it can thereby become active, showing psychostimulant effects, when combination drug with a monoamine oxidase inhibitor (MAOI), specifically monoamine oxidase B (MAO-B) enzyme inhibitor like selegiline. (1996). 9783211828915 ISBN 9783211828915 Oral 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. Misuse potential of phenethylamine in combination with selegiline has also been reported.
The values of phenethylamine include 175mg/kg i.p. in mice, 320mg/kg s.c. in mice, 100mg/kg i.v. in mice, 100mg/kg parenterally in mice, 39mg/kg intracervically in mice, and 200mg/kg i.p. in guinea pigs. Its values include 800mg/kg p.o. in rats, 100mg/kg i.p. in rats, 450μg/kg s.c. in rats, and 300mg/kg via an unspecified route in mice.
When the initial phenylethylamine concentration in the brain is low, brain levels can be increased when taking a monoamine oxidase inhibitor (MAOI), particularly a MAO-B inhibitor, and by times when the initial concentration is high.
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