Phenethylamine

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Not to be confused with 1-phenylethylamine.
Phenethylamine
Phenethylamine2DCSD.svg
Phenethylamine3DanJ.gif
Systematic (IUPAC) name
2-phenylethanamine
Clinical data
Legal status Uncontrolled
Dependence liability Moderate
Routes Oral
Pharmacokinetic data
Metabolism MAO-A, MAO-B, PNMT, ALDH, DBH, CYP2D6
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]

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 stimulants, psychedelics, 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 suffering from 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]

Trace amine and catecholamine biosynthesis in humans

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.[25] Consumption of large quantities by mice has been associated with Parkinson's disease-like neurological deficits.[26]

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 (14 May 1996). "Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.". Proceedings of the National Academy of Sciences of the United States of America 93 (10): 5166–71. 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. ^ 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. 
  26. ^ 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. 

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