Phenethylamine

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Phenethylamine
Image of the phenethylamine skeleton
Ball-and-stick model of phenethylamine
Systematic (IUPAC) name
2-phenylethanamine
Clinical data
Pronunciation /fɛnˈɛθələmn/
Legal status
  • AU: Unscheduled
  • CA: Unscheduled
  • UK: Unscheduled
  • US: Unscheduled
  • UN: Unscheduled
Dependence
liability
Psychological: low–moderate
Physical: none
Addiction
liability
None (without an MAO-B inhibitor)
Moderate (with an MAO-B inhibitor)
Routes of
administration
Oral
Pharmacokinetic data
Metabolism Primarily:
MAO-B and ALDH
Minor routes:
MAO-A, SSAOs, PNMT, AANAT, FMO3, and others
Biological half-life Exogenous: 5–10 minutes[1]
Endogenous: ~30 seconds[2]
Identifiers
CAS Number 64-04-0 YesY
ATC code none
PubChem CID: 1001
IUPHAR/BPS 2144
DrugBank DB04325 YesY
ChemSpider 13856352 YesY
UNII 327C7L2BXQ YesY
KEGG C05332 YesY
ChEBI CHEBI:18397 YesY
ChEMBL CHEMBL610 YesY
NIAID ChemDB 018561
Synonyms 1-amino-2-phenylethane
Chemical data
Formula C8H11N
Molecular mass 121.18 g/mol
Physical data
Density 0.9640 g/cm3
Melting point −60 °C (−76 °F) [3]
Boiling point 197.5 °C (387.5 °F) [3]
  (verify)

Phenethylamine (PEA), also known as β-phenylethylamine (β-PEA) and 2-phenylethylamine is an organic compound and a natural monoamine alkaloid, a trace amine, and also the name of a class of chemicals with many members that are well known for their psychoactive and stimulant effects.[4]

Phenylethylamine functions as a monoaminergic neuromodulator and, to a lesser extent, a neurotransmitter in the human central nervous system.[5] It is biosynthesized from the amino acid L-phenylalanine by enzymatic decarboxylation via the enzyme aromatic L-amino acid decarboxylase.[6] In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation. It is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, orally ingested phenethylamine experiences extensive first-pass metabolism by monoamine oxidase B (MAO-B) and then aldehyde dehydrogenase (ALDH), which metabolize it into phenylacetic acid.[7] This prevents significant concentrations from reaching the brain when taken in low doses.[8][9]

The group of phenethylamine derivatives is referred to as the phenethylamines. Substituted phenethylamines, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include empathogens, stimulants, psychedelics, anxiolytics (hypnotics) and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others.

Natural occurrence

Phenethylamine is widely distributed throughout the plant kingdom and also present in animals, such as humans;[6][10][11] it is also produced by certain fungi and bacteria (genus: Lactobacillus, Clostridium, Pseudomonas, and Enterobacteriaceae) and acts as a potent anti-microbial against certain pathogenic strains of Escherichia coli (e.g., the O157:H7 strain) at sufficient concentrations.[11][12]

Physical and chemical properties

Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group.[13] It is a colourless liquid at room temperature that has a fishy odour and is soluble in water, ethanol and ether.[13] Its density is 0.964 g/ml and its boiling point is 195 °C.[13] Upon exposure to air, it forms a solid carbonate salt[clarification needed] with carbon dioxide.[14] Phenethylamine is strongly basic, pKb = 4.17 (or pKa = 9.83), as measured using the HCl salt and forms a stable crystalline hydrochloride salt with a melting point of 217 °C.[13][15]

Synthesis

One method for preparing β-phenethylamine, set forth in J. C. Robinson's 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.[16]

A much more convenient method for the synthesis of β-phenethylamine is the reduction of ω-nitrostyrene by lithium aluminum hydride in ether, whose successful execution was first reported by R. F. Nystrom and W. G. Brown in 1948.[17] Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.[18]

Electrosynthesis of phenethylamine from benzyl cyanide[18]

Pharmacology

Pharmacodynamics

Phenethylamine pharmacodynamics in a TAAR1–dopamine neuron
v · t · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Both amphetamine and phenethylamine induce neurotransmitter release from VMAT2[19][20][21] and bind to TAAR1.[22][23] When either binds to TAAR1, it reduces neuron firing rate and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation.[22][23] Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport.[22][23]

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, releases norepinephrine and dopamine.[19][22][23] Phenethylamine also appears to induce acetylcholine release via a glutamate-mediated mechanism.[24]

Reviews that cover attention deficit hyperactivity disorder (ADHD) and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine content in ADHD individuals when compared with controls.[11][25] In treatment responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine content.[11][25] An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[11][25]

Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary phenylacetic acid, the primary metabolite of phenethylamine.[2][26][27] 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;[2][26][27] 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.[2][26][27][28] 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.[28] 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.[2][26][27]

Pharmacokinetics

Human biosynthesis pathway for trace amines and catecholamines[2][28]
The image above contains clickable links
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine.

By oral route, phenylethylamine's half-life is 5–10 minutes;[1] endogenously produced PEA in catecholamine neurons has a half-life of roughly 30 seconds.[2] It is metabolized by phenylethanolamine N-methyltransferase,[2][29] MAO-A,[9] MAO-B,[8] semicarbazide-sensitive amine oxidases (SSAOs),[30] aldehyde dehydrogenase,[31] and flavin-containing monooxygenase 3.[32] N-methylphenethylamine, an isomer of amphetamine, is produced in humans via the metabolism of phenethylamine by phenylethanolamine N-methyltransferase.[2][28][29] When the initial phenylethylamine brain concentration is low, brain levels can be increased 1000-fold when taking a monoamine oxidase inhibitor (MAOI), particularly a MAO-B inhibitor, and by 3–4 times when the initial concentration is high.[33] β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism and subsequent aldehyde dehydrogenase metabolism.[7] In humans, phenylacetaldehyde is the intermediate product which is produced by monoamine oxidase and then further metabolized into β-phenylacetic acid by aldehyde dehydrogenase.

See also

References

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  4. Glen R. Hanson; Peter J. Venturelli; Annette E. Fleckenstein (3 November 2005). Drugs and society (Ninth Edition). Jones and Bartlett Publishers. ISBN 978-0-7637-3732-0. Retrieved 19 April 2011.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. Sabelli, HC; Mosnaim, AD; Vazquez, AJ; Giardina, WJ; Borison, RL; Pedemonte, WA (1976). "Biochemical plasticity of synaptic transmission: A critical review of Dale's Principle". Biological Psychiatry. 11 (4): 481–524. PMID 9160.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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  8. 8.0 8.1 Yang, HY; Neff, NH (1973). "Beta-phenylethylamine: A specific substrate for type B monoamine oxidase of brain". The Journal of Pharmacology and Experimental Therapeutics. 187 (2): 365–71. PMID 4748552.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. 9.0 9.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
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  12. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
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  14. O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1296
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  17. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
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  21. Offermanns, S; Rosenthal, W, eds. (2008). Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 3540389164.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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External links