Phenethylamine

Source: Wikipedia, the free encyclopedia.
Not to be confused with
1-phenylethylamine or phenylalanine
.
This article is about a specific substance. For the class of substances, see substituted phenethylamine.

Phenethylamine
SSAOs (AOC2 & AOC3),[5][7] PNMT,[3][4][5] AANAT,[5] FMO3,[8][9] and others
Legal status
Legal status
  • AU: Unscheduled
  • CA: Unscheduled
  • NZ: Unscheduled
  • UK: Unscheduled
  • US: Unscheduled
  • UN: Unscheduled
Renal
(kidneys)
Identifiers
  • 2-Phenylethan-1-amine
JSmol)
Density0.9640 g/cm3
Melting point−60 °C (−76 °F) [11]
Boiling point195 °C (383 °F) [11]
  • NCCc1ccccc1
  • InChI=1S/C8H11N/c9-7-6-8-4-2-1-3-5-8/h1-5H,6-7,9H2 checkY
  • Key:BHHGXPLMPWCGHP-UHFFFAOYSA-N checkY
  (verify)

Phenethylamine

fermentation
.

Phenethylamine is sold as a

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.[5] This means that for significant concentrations to reach the brain, the dosage must be higher than for other methods of administration.[5][6][16] Some authors postulated its role in people's falling-in-love without substantiating it with any direct evidence.[17][18]

Phenethylamines, or more properly,

empathogens, stimulants, psychedelics, anorectics, bronchodilators, decongestants, and/or antidepressants
, among others.

Natural occurrence

Phenethylamine is produced by a wide range of species throughout the plant and animal kingdoms, including humans;

fungi and bacteria (genera: Lactobacillus, Clostridium, Pseudomonas and the family Enterobacteriaceae) and acts as a potent antimicrobial against certain pathogenic strains of Escherichia coli (e.g., the O157:H7 strain) at sufficient concentrations.[20]

Chemistry

PEA powder and crystals

Phenethylamine is a primary amine, the amino-group being attached to a

benzene ring through a two-carbon, or ethyl group.[21] It is a colourless liquid at room temperature that has a fishy odor, and is soluble in water, ethanol and ether.[21] Its density is 0.964 g/ml and its boiling point is 195 °C.[11] Upon exposure to air, it combines with carbon dioxide to form a solid carbonate salt.[22] 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.[21][23]

Substituted derivatives

Main article: Substituted phenethylamine

Substituted phenethylamines are a

chemical class of organic compounds based upon the phenethylamine structure;[note 2] the class is composed of all the derivative compounds of phenethylamine which can be formed by replacing, or substituting, one or more hydrogen atoms in the phenethylamine core structure with substituents
.

Many substituted phenethylamines are psychoactive drugs, which belong to a variety of different drug classes, including

vasopressors (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 compounds – including hormones, monoamine neurotransmitters, and many trace amines (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 cathinones, 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.

Synthesis

One method for preparing β-phenethylamine, set forth in J. C. Robinson and H. R. Snyder's Organic Syntheses (published 1955), involves the reduction of

catalyst, at a temperature of 130 °C and a pressure of 13.8 MPa. Alternative syntheses are outlined in the footnotes to this preparation.[24]

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.[25]

Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.[26]

Electrosynthesis of phenethylamine from benzyl cyanide[26]

Assembling phenethylamine structures for synthesis of compounds such as epinephrine, amphetamines, tyrosine, and dopamine by adding the beta-aminoethyl side chain to the

Suzuki cross-coupling.[27]

Detection in body fluids

Reviews that cover attention deficit hyperactivity disorder (ADHD) and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine concentrations in ADHD individuals when compared with controls.[28] In treatment-responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine concentration.[28] An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[28]

Thirty minutes of moderate- to high-intensity physical exercise has been shown to induce an increase in urinary

euphoriants.[3][29][30]

Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.[21][31]

Pharmacology

See also: Neurobiological effects of physical exercise § β-Phenylethylamine

Pharmacodynamics

Phenethylamine pharmacodynamics in a TAAR1–dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Both amphetamine and phenethylamine induce neurotransmitter release from
VMAT2[12][33][34] and bind to TAAR1.[13][35] 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.[13][35] Phosphorylated DAT then either operates in reverse or withdraws into the axon terminal and ceases transport.[13][35]

Phenethylamine, being similar to

releases norepinephrine and dopamine.[12][13][35] Phenethylamine also appears to induce acetylcholine release via a glutamate-mediated mechanism.[36]

Phenethylamine has been shown to bind to

agonist.[2] β-PEA is also an odorant binding TAAR4 in mice thought to mediate predator avoidance.[37]

Pharmacokinetics

Biosynthetic pathways for catecholamines and trace amines in the human brain[38][39][40]
The image above contains clickable links
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.

By

β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism and subsequent aldehyde dehydrogenase metabolism.[5] Phenylacetaldehyde is the intermediate product which is produced by monoamine oxidase and then further metabolized into β-phenylacetic acid by aldehyde dehydrogenase.[5][43]

When the initial phenylethylamine concentration in the brain 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.[44]

See also

Notes

  1. ^ Synonyms and alternate spellings include: phenylethylamine, β-phenylethylamine (β-PEA), 2-phenylethylamine, 1-amino-2-phenylethane, and 2-phenylethan-1-amine.
  2. ^ In other words, all of the compounds that belong to this class are structural analogs of phenethylamine.

References

  1. ^
    PMID 27092049
    . Furthermore, evidence has accrued on the ability of TAs to modulate brain reward (i.e., the subjective experience of pleasure) and reinforcement (i.e., the strengthening of a conditioned response by a given stimulus; Greenshaw, 2021), suggesting the involvement of the TAs in the neurological adaptations underlying drug addiction, a chronic relapsing syndrome characterized by compulsive drug taking, inability to control drug intake and dysphoria when access to the drug is prevented (Koob, 2009). Consistent with its hypothesized role as "endogenous amphetamine," β-PEA was shown to possess reinforcing properties, a defining feature that underlies the abuse liability of amphetamine and other psychomotor stimulants. β-PEA was also as effective as amphetamine in its ability to produce conditioned place preference (i.e., the process by which an organism learns an association between drug effects and a particular place or context) in rats (Gilbert and Cooper, 1983) and was readily self-administered by dogs that had a stable history (i.e., consisting of early acquisition and later maintenance) of amphetamine or cocaine self-administration (Risner and Jones, 1977; Shannon and Thompson, 1984). In another study, high concentrations of β-PEA dose-dependently maintained responding in monkeys that were previously trained to self-administer cocaine, and pretreatment with a MAO-B inhibitor, which delayed β-PEA deactivation, further increased response rates (Bergman et al., 2001).
  2. ^
    PMID 27424325
    .
  3. ^
    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].
  4. ^
    PMID 19948186
    . Trace amines are metabolized in the mammalian body via monoamine oxidase
  5. ^
    Human Metabolome Database, HMDB
    . 5.0.
  6. ^
    S2CID 36099388
    .
  7. ^
    S2CID 30090890
    . The preferred in vitro substrates of AOC2 were found to be 2-phenylethylamine, tryptamine and p-tyramine instead of methylamine and benzylamine, the favored substrates of AOC3.
  8. ^
    PMID 15922018
    . The biogenic amines, phenethylamine and tyramine, are N-oxygenated by FMO to produce the N-hydroxy metabolite, followed by a rapid second oxygenation to produce the trans-oximes (Lin & Cashman, 1997a, 1997b). This stereoselective N-oxygenation to the trans-oxime is also seen in the FMO-dependent N-oxygenation of amphetamine (Cashman et al., 1999) ... Interestingly, FMO2, which very efficiently N-oxygenates N-dodecylamine, is a poor catalyst of phenethylamine N-oxygenation. The most efficient human FMO in phenethylamine N-oxygenation is FMO3, the major FMO present in adult human liver; the Km is between 90 and 200 μM (Lin & Cashman, 1997b).
  9. ^
    PMID 27513517
    . TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). ... FMO3 catalyzes the oxidation of catecholamine or catecholamine-releasing vasopressors, including tyramine, phenylethylamine, adrenaline, and noradrenaline [32, 33].
  10. ^ a b "Phenethylamine: Pharmacology and Biochemistry". PubChem. United States National Library of Medicine – National Center for Biotechnology Information. Plasma Pharmacokinetics of PEA Could Be Described By 1st-Order Kinetics With Estimated T/2 of Approx 5-10 Min.
  11. ^ a b c "Chemical and Physical Properties". Phenethylamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information.
  12. ^
    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...
  13. ^
    PMID 21073468
    .
  14. PMID 9160
    .
  15. ^
    PMID 15228583
    .
  16. ^
    PMID 4748552
    .
  17. ISSN 0002-7863
    .
  18. S2CID 24651931
    .
  19. doi:10.1016/0031-9422(77)83004-5
    .
  20. PMID 23896151
    . Acetoacetic acid (AAA) and ß-phenylethylamine (PEA) performed best in this experiment. On beef meat pieces, PEA reduced the bacterial cell count by 90% after incubation of the PEA-treated and E. coli-contaminated meat pieces at 10°C for one week.
  21. ^ a b c d e "Phenethylamine". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 28 December 2016.
  22. ^ O'Neil MJ, ed. (2001). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals (13th ed.). Whitehouse Station, NJ: Merck and Co., Inc. p. 1296.
  23. doi:10.1021/ja01150a055
    .
  24. ^ Robinson JC, Snyder HR (1955). "β-Phenylethylamine" (PDF). Organic Syntheses, Collected Volume. 3: 720.
  25. PMID 18102934
    .
  26. ^
    S2CID 96102382
    .
  27. PMID 17217265
    .
  28. ^
    PMID 23021477
    . 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
  29. ^
    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.
  30. ^
    PMID 18473983
    . It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].
  31. PMID 7063846
    . The urinary excretion rate of the endogenous, amphetamine-like substance beta-phenethylamine was markedly elevated in human subjects in association with an initial parachuting experience. The increases were delayed in most subjects and were not correlated with changes in urinary pH or creatinine excretion.
  32. ^ "2-PHENYLETHYLAMINE". United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Retrieved 20 September 2016.
  33. PMID 8643547
    .
  34. ISBN 978-3540389163
    .
  35. ^
    PMID 25426030
    . TAAR1 activity appears to depress monoamine transport and limit dopaminergic and serotonergic neuronal firing rates via interactions with presynaptic D2 and 5-HT1A autoreceptors, respectively (Wolinsky et al., 2007; Lindemann et al., 2008; Xie and Miller, 2008; Xie et al., 2008; Bradaia et al., 2009; Revel et al., 2011; Leo et al., 2014).  ... TAAR1 and TAAR4 labeling in all neurons appeared intracellular, consistent with previous reported results for TAAR1 (Miller, 2011). A cytoplasmic location of ligand and receptor (e.g., tyramine and TAAR1) supports intracellular activation of signal transduction pathways, as suggested previously (Miller, 2011). ... Additionally, once transported intracellularly, they could act on presynaptic TAARs to alter basal activity (Miller, 2011). ... As reported for TAAR1 in HEK cells (Bunzow et al., 2001; Miller, 2011), we observed cytoplasmic labeling for TAAR1 and TAAR4, both of which are activated by the TAs (Borowsky et al., 2001). A cytoplasmic location of the ligand and the receptor (e.g., tyramine and TAAR1) would support intracellular activation of signal transduction pathways (Miller, 2011). Such a co-localization would not require release from vesicles and could explain why the TAs do not appear to be found there (Berry, 2004; Burchett and Hicks, 2006).
  36. doi:10.5350/KPB-BCP201121113
    . PEA can also stimulate acetylcholine release through activation of glutamatergic signaling pathways (21), and PEA and p-TA have been reported to depress GABAB receptor-mediated responses in dopaminergic neurons (22,23). Although PEA, T and p-TA have been reported to be present in synaptosomes (nerve ending preparations isolated during homogenization and centrifugation of brain tissue) (24), research with reserpine and neurotoxins suggests that m- and p-TA may be stored in vesicles while PEA and T are not (25–27). ... the antidepressant effects of exercise have been suggested to be due to an elevation of PEA (57). l-Deprenyl (selegiline), a selective inhibitor of MAO-B, is used in the treatment of Parkinson's disease and produces a marked increase in brain levels of PEA relative to other amines (20,58). ... Interestingly, the gene for aromatic amino acid decarboxylase (AADC), the major enzyme involved in the synthesis of the trace amines, is located in the same region of chromosome 7 that has been proposed as a susceptibility locus for ADHD (50)
  37. PMID 25616211
    .
  38. PMID 19948186
    .
  39. PMID 15860375
    .
  40. PMID 24374199
    .
  41. ^
    S2CID 1015819
    .
  42. ^ "EC 2.3.1.87 – Aralkylamine N-acetyltransferase". BRENDA. Technische Universität Braunschweig. July 2014. Retrieved 10 November 2014.
  43. ^ "Aldehyde dehydrogenase – Homo sapiens". BRENDA. Technische Universität Braunschweig. January 2015. Retrieved 13 April 2015.
  44. PMID 361043
    .

External links
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