Phenethylamine

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Not to be confused with 1-phenylethylamine.
Phenethylamine
Phenethylamine2DCSD.svg
Phenethylamine-3D-spacefill.png
Systematic (IUPAC) name
2-phenylethanamine
Clinical data
Legal status
  • Uncontrolled
Moderate
Routes Oral
Pharmacokinetic data
Metabolism MAO-A, MAO-B, PNMT, ALDH, DBH, CYP2D6, AANAT
Half-life ~5–10 minutes
Identifiers
CAS number 64-04-0 YesY
ATC code None
PubChem CID 1001
IUPHAR ligand 2144
ChemSpider 13856352 YesY
UNII 327C7L2BXQ YesY
ChEBI CHEBI:18397 YesY
ChEMBL CHEMBL610 YesY
NIAID ChemDB 018561
Synonyms 1-amino-2-phenylethane
Chemical data
Formula C8H11N 
Mol. mass 121.18 g/mol
Physical data
Boiling point 195 °C (383 °F)
 YesY (what is this?)  (verify)

Phenethylamine /fɛnˈɛθələmn/ (PEA), β-phenethylamine, or 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.[1]

Phenylethylamine functions as a neuromodulator or neurotransmitter in the mammalian central nervous system.[2] It is biosynthesized from the amino acid L-phenylalanine by enzymatic decarboxylation via the enzyme aromatic L-amino acid decarboxylase.[3] 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), which turns it into phenylacetic acid. This prevents significant concentrations from reaching the brain when taken in low doses.[4][5][clarification needed]

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.

Occurrence[edit]

Phenethylamine is widely distributed throughout the plant kingdom and also present in animals, such as humans.[3][6]

Physical and chemical properties[edit]

Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group.[7] It is a colourless liquid at room temperature that has a fishy odour and is soluble in water, ethanol and ether.[7] Upon exposure to air, it forms a solid carbonate salt with carbon dioxide.[7] 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.[7][8] Its density is 0.964 g/ml and its boiling point is 195 °C.[7]

Synthesis[edit]

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.[9] 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.[10]

Pharmacology[edit]

Phenethylamine, similar to amphetamine in its action, releases norepinephrine and dopamine.[11][12][13] When taken orally, though, it is rapidly metabolized.[14]

Abnormally low concentrations of endogenous phenethylamine are found in those with attention deficit hyperactivity disorder (ADHD),[15] whereas abnormally high concentrations have been discovered to have a strong, positive correlation with the incidence of schizophrenia.[16]

Phenethylamine and amphetamine pharmacodynamics in a TAAR1–dopamine neuron

A pharmacodynamic model of amphetamine and TAAR1
via AADC
Both amphetamine and phenethylamine induce neurotransmitter release from VMAT2[17][18][19] and bind to TAAR1.[20] When either binds to TAAR1, it reduces dopamine receptor firing rate and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation.[20] Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport.[20]

Pharmacokinetics[edit]

Phenylethylamine's half-life is 5 to 10 minutes.[21] It is metabolized by phenylethanolamine N-methyltransferase,[22] MAO-A,[5] MAO-B,[4] aldehyde dehydrogenase and dopamine-beta-hydroxylase.[21] N-methylphenethylamine, an isomer of amphetamine, is produced when phenethylamine is used as a substrate by phenylethanolamine N-methyltransferase.[22][23] When the initial phenylethylamine brain concentration is low, brain levels can be increased 1000-fold when taking an MAO inhibitor (MAOI) and by 3–4 times when the initial concentration is high.[24]

Human biosynthesis pathway for trace amines and catecholamines[27]

In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine. Abbreviations:
DBH: Dopamine β-hydroxylase;
AADC:Aromatic L-amino acid decarboxylase;
AAAH: (Biopterin-dependent) aromatic amino acid hydroxylase;
COMT: Catechol O-methyltransferase;
PNMT: Phenylethanolamine N-methyltransferase

Toxicity[edit]

Acute toxicity studies on phenethylamine show an LD50 = 100 mg/kg, after intravenous administration to mice.[28] Consumption of large quantities by mice has been associated with Parkinson's disease-like neurological deficits.[29]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ a b Berry, MD (July 2004). "Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators." (PDF). Journal of Neurochemistry 90 (2): 257–71. doi:10.1111/j.1471-4159.2004.02501.x. PMID 15228583. 
  4. ^ a b 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. 
  5. ^ a b Suzuki, O.; Katsumata, Y.; Oya, M. (1981). "Oxidation of ?-Phenylethylamine by Both Types of Monoamine Oxidase: Examination of Enzymes in Brain and Liver Mitochondria of Eight Species". Journal of Neurochemistry 36 (3): 1298–301. doi:10.1111/j.1471-4159.1981.tb01734.x. PMID 7205271. 
  6. ^ Smith, Terence A. (1977). "Phenethylamine and related compounds in plants". Phytochemistry 16 (1): 9–18. doi:10.1016/0031-9422(77)83004-5. 
  7. ^ a b c d e United States Government. "Phenethylamine". PubChem Compound. Bethesda, USA: National Center for Biotechnology Information, U.S. National Library of Medicine. 
  8. ^ Leffler, Esther B.; Spencer, Hugh M.; Burger, Alfred (1951). "Dissociation Constants of Adrenergic Amines". Journal of the American Chemical Society 73 (6): 2611–3. doi:10.1021/ja01150a055. 
  9. ^ Robinson, J. C.; Snyder, H. R. (1955). "β-Phenylethylamine". Organic Syntheses, Coll 3: 720. 
  10. ^ Nystrom, Robert F.; Brown, Weldon G. (1948). "Reduction of Organic Compounds by Lithium Aluminum Hydride. III. Halides, Quinones, Miscellaneous Nitrogen Compounds1". Journal of the American Chemical Society 70 (11): 3738–40. doi:10.1021/ja01191a057. PMID 18102934. 
  11. ^ Nakamura, Masato; Ishii, Akira; Nakahara, Daiichiro (1998). "Characterization of β-phenylethylamine-induced monoamine release in rat nucleus accumbens: A microdialysis study". European Journal of Pharmacology 349 (2–3): 163–9. doi:10.1016/S0014-2999(98)00191-5. PMID 9671094. 
  12. ^ EM Parker and LX Cubeddu (April 1988). "Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding". Journal of Pharmacology and Experimental Therapeutics 245 (1): 199–210. ISSN 0022-3565. PMID 3129549. 
  13. ^ Paterson, I. A. (1993). "The potentiation of cortical neuron responses to noradrenaline by 2-phenylethylamine is independent of endogenous noradrenaline". Neurochemical Research 18 (12): 1329–36. doi:10.1007/BF00975055. PMID 8272197. 
  14. ^ Shulgin, Alexander; Ann Shulgin. "Erowid Online Books : "PIHKAL" – #142 PEA". Retrieved 13 May 2010. 
  15. ^ Baker, G.B.; Bornstein, R.A.; Rouget, A.C.; Ashton, S.E.; Van Muyden, J.C.; Coutts, R.T. (1991). "Phenylethylaminergic mechanisms in attention-deficit disorder". Biological Psychiatry 29 (1): 15–22. doi:10.1016/0006-3223(91)90207-3. PMID 2001444. 
  16. ^ Potkin, S.; Karoum, F; Chuang, L.; Cannon-Spoor, H.; Phillips, I; Wyatt, R. (1979). "Phenylethylamine in paranoid chronic schizophrenia". Science 206 (4417): 470–1. doi:10.1126/science.504988. PMID 504988. 
  17. ^ Offermanns, S; Rosenthal, W, eds. (2008). Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 3540389164. 
  18. ^ Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E (May 1996). "Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter". Proc. Natl. Acad. Sci. U.S.A. 93 (10): 5166–5171. doi:10.1073/pnas.93.10.5166. PMC 39426. PMID 8643547. 
  19. ^ Quick, Michael W., ed. (2002). Transmembrane Transporters. Hoboken, NJ: John Wiley & Sons. p. 192. ISBN 0471461237. 
  20. ^ a b c Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468. 
  21. ^ a b Sabelli, Hector C.; J. I. Javaid (1 February 1995). "Phenylethylamine modulation of affect: therapeutic and diagnostic implications". J Neuropsychiatry Clin Neurosci 7 (1): 6–14. ISSN 0895-0172. PMID 7711493. 
  22. ^ a b Pendleton, Robert G.; Gessner, George; Sawyer, John (1980). "Studies on lung N-methyltransferases, a pharmacological approach". Naunyn-Schmiedeberg's Archives of Pharmacology 313 (3): 263–8. doi:10.1007/BF00505743. PMID 7432557. 
  23. ^ Broadley, Kenneth J. (2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics 125 (3): 363–75. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. 
  24. ^ Sabelli, Hector C.; Borison, Richard L.; Diamond, Bruce I.; Havdala, Henri S.; Narasimhachari, Nedathur (1978). "Phenylethylamine and brain function". Biochemical Pharmacology 27 (13): 1707–11. doi:10.1016/0006-2952(78)90543-9. PMID 361043. 
  25. ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. 
  26. ^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. 
  27. ^ [25][26]
  28. ^ Lands, AM; Grant, JI (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives". The Journal of Pharmacology and Experimental Therapeutics 106 (3): 341–5. PMID 13000630. 
  29. ^ Borah, A; Paul, R; Mazumder, MK; Bhattacharjee, N (October 2013). "Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration: implications for the pathogenesis of Parkinson's disease.". Neuroscience Bulletin 29 (5): 655–60. doi:10.1007/s12264-013-1330-2. PMID 23575894. 

External links[edit]