Phenethylamine

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Not to be confused with 1-phenylethylamine.
Phenethylamine
Phenethylamine2DCSD.svg
Ball-and-stick model of phenethylamine
Systematic (IUPAC) name
2-phenylethanamine
Clinical data
Legal status
Psychological: Moderate
Physical: None
Moderate
Routes Oral
Pharmacokinetic data
Metabolism MAO-A, MAO-B, PNMT, ALDH, DBH, CYP2D6, AANAT
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 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 
Molecular mass 121.18 g/mol
Physical data
Melting point −60 °C (−76 °F) [3]
Boiling point 197.5 °C (387.5 °F) [3]
 YesY (what is this?)  (verify)

Phenethylamine /fɛnˈɛθələmn/ (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 neuromodulator or neurotransmitter in the mammalian 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), which turns 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.

Occurrence[edit]

Phenethylamine is widely distributed throughout the plant kingdom and also present in animals, such as humans.[6][10]

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.[11] It is a colourless liquid at room temperature that has a fishy odour and is soluble in water, ethanol and ether.[11] Upon exposure to air, it forms a solid carbonate salt with carbon dioxide.[11] 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.[11][12] Its density is 0.964 g/ml and its boiling point is 195 °C.[11]

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.[13] 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.[14]

Pharmacology[edit]

Pharmacodynamics[edit]

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, releases norepinephrine and dopamine.[15][16][17]

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.[18][19] In treatment responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine content.[18][19] An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[18]

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.[20][2][21] 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][20][21] 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][20][21][22] 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.[22] 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][20][21]

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[23][24][25] and bind to TAAR1.[26] 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.[26] Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport.[26]

Pharmacokinetics[edit]

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,[27] MAO-A,[9] MAO-B,[8] aldehyde dehydrogenase and dopamine-beta-hydroxylase.[28] N-methylphenethylamine, an isomer of amphetamine, is produced when phenethylamine is used as a substrate by phenylethanolamine N-methyltransferase.[27][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.[30] β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism.[7]

Human biosynthesis pathway for trace amines and catecholamines[33]

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

See also[edit]

References[edit]

  1. ^ a b "Pharmacology and Biochemistry". Phenethylamine. PubChem Compound. NCBI. Retrieved 5 March 2015. 
  2. ^ a b c d e f Lindemann L, Hoener M (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. The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55]. 
  3. ^ a b "Chemical and Physical Properties". Phenethylamine. Pubchem Compound. NCBI. Retrieved 17 February 2015. 
  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. 
  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. 
  6. ^ 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. 
  7. ^ a b "Phenethylamine". Human Metabolome Database. Retrieved 17 February 2015. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ Smith, Terence A. (1977). "Phenethylamine and related compounds in plants". Phytochemistry 16 (1): 9–18. doi:10.1016/0031-9422(77)83004-5. 
  11. ^ a b c d e United States Government. "Phenethylamine". PubChem Compound. Bethesda, USA: National Center for Biotechnology Information, U.S. National Library of Medicine. 
  12. ^ 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. 
  13. ^ Robinson, J. C.; Snyder, H. R. (1955). "β-Phenylethylamine". Organic Syntheses, Coll 3: 720. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ a b c Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry 51 (10): 1003–1019.e20. doi:10.1016/j.jaac.2012.08.015. PMID 23021477. Retrieved 30 June 2014. Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls. ... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,20,60 suggesting that ADHD treatments normalize PEA levels. ... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,20,57,58 for treatment efficacy,20,60 and associated with symptoms of inattentivenesss.59 ... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110 
  19. ^ a b Irsfeld M, Spadafore M, Prüß BM (September 2013). "β-phenylethylamine, a small molecule with a large impact". Webmedcentral 4 (9). PMC 3904499. PMID 24482732. 
  20. ^ a b c d Szabo A, Billett E, Turner J (2001). "Phenylethylamine, a possible link to the antidepressant effects of exercise?". Br J Sports Med 35 (5): 342–343. PMC 1724404. PMID 11579070. The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. ... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels3 , and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise. ... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise. 
  21. ^ a b c d Berry M (2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials 2 (1): 3–19. PMID 18473983. It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151]. 
  22. ^ a b 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. Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It 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 deaminated in the gut as it is a selective substrate for MAO-B which is not 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 (Berry, 2004). 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 ...
     
  23. ^ Wimalasena K (July 2011). "Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry". Med Res Rev 31 (4): 483–519. doi:10.1002/med.20187. PMC 3019297. PMID 20135628. Phenylethylamine (10), amphetamine [AMPH (11 & 12)], methylenedioxy methamphetamine [METH (13)] and N-methyl-4-phenylpyridinium (15) are all more potent inhibitors of VMAT2... 
  24. ^ 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. 
  25. ^ Offermanns, S; Rosenthal, W, eds. (2008). Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 3540389164. 
  26. ^ 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. 
  27. ^ 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. 
  28. ^ 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. 
  29. ^ 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. 
  30. ^ 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. 
  31. ^ 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. 
  32. ^ 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. 
  33. ^ [31][32]

External links[edit]