Chemistry:Etilamfetamine

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Etilamfetamine, also known as N-ethylamphetamine and formerly sold under the brand names Apetinil and Adiparthrol, is a stimulant drug of the amphetamine family. It was invented in the early 20th century and was subsequently used as an anorectic or appetite suppressant in the 1950s,[1] but was not as commonly used as other amphetamines such as amphetamine, methamphetamine, and benzphetamine, and was largely discontinued once newer drugs such as phenmetrazine were introduced.

Pharmacology

Pharmacodynamics

Monoamine releasing agent

Ethylamphetamine is a potent dopamine releasing agent (DRA) in vitro, with an EC50 of 88.5 nM.[2] This is about 10-fold lower than the EC50 of dextroamphetamine.[2] The EC50 values of ethylamphetamine for induction of norepinephrine and serotonin release were not reported.[2] However, the EC50 values of its dextrorotatory enantiomer dextroethylamphetamine have been reported and were 44.1 nM, 28.8 nM, and 333 nM for norepinephrine, dopamine, and serotonin, respectively.[3][4] Hence, dextroethylamphetamine acts as a norepinephrine–dopamine releasing agent (NDRA) with weak effects on serotonin.[3][4]

In terms of structure–activity relationships, the potency of amphetamines as dopamine releasing agents and reuptake inhibitors decreases with increasing N-alkyl chain length.[2] That is, the order of potency of N-alkylated amphetamines is as follows: amphetamine > methamphetamine > ethylamphetamine > propylamphetamine > butylamphetamine.[2] Propylamphetamine is a weak dopamine reuptake inhibitor rather than releaser, whereas butylamphetamine is completely inactive as a dopamine releaser or reuptake inhibitor.[2] The same relationship, for monoamine release and reuptake inhibition generally, has been shown with 4-methylamphetamine and its N-alkylated derivatives like 4-methylmethamphetamine and so forth.[5][6]

Monoamine release of ethylamphetamine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Phenethylamine 10.9 39.5 >10,000 [2][7][8]
d-Amphetamine 6.6–10.2 5.8–24.8 698–1,765 [9][10][8][11]
d-Methamphetamine 12.3–14.3 8.5–40.4 736–1,292 [9][12][8][11]
Ethylamphetamine ND 88.5 ND [2]
  d-Ethylamphetamine 28.8 44.1 333.0 [3][4]
Propylamphetamine ND RI (1,013) ND [2]
Butylamphetamine ND IA (>10,000) ND [2]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:[13][14]

Other actions

Ethylamphetamine is inactive as an agonist of the mouse and human trace amine-associated receptor 1 (TAAR1), whereas findings in the case of the rat TAAR1 are conflicting.[15][16] In one study, its Ki was 2,500 nM and its EC50 (Emax) was 880 nM (62%) at the rat TAAR1 (i.e., it was a partial agonist), whereas its Ki and/or EC50 values at the mouse and human TAAR1 were >10,000 nM.[15] In another study however, ethylamphetamine showed very little capacity to activate the rat TAAR1.[15]

Pharmacokinetics

Ethylamphetamine can be N-dealkylated into amphetamine (5–18% excreted in urine after 24 hours).[17] As such, amphetamine may contribute to its effects in vivo.[17]

Chemistry

The molecular structure of ethylamphetamine is analogous to methamphetamine, with an ethyl group in place of the methyl group.[Note 1] It can also be considered a substituted amphetamine, with an ethyl group on the amphetamine backbone.[Note 2][Note 3]

Analogues of ethylamphetamine include amphetamine, methamphetamine, propylamphetamine, isopropylamphetamine, butylamphetamine, fenfluramine (3-trifluoromethyl-N-ethylamphetamine), dimethylamphetamine, and 3-fluoroethamphetamine (3-fluoro-N-ethylamphetamine), among others.

Society and culture

Recreational use

Ethylamphetamine can be used as a recreational drug and, while its prevalence is less than amphetamine's, it is still encountered as a substance taken for recreational purposes. Ethylamphetamine produces effects similar to amphetamine and methamphetamine, though it is of lower potency.[citation needed]

Notes

  1. ↑ Amphetamine is a substituted phenethylamine with a methyl group at RA position.
  2. ↑ The ethyl group of ethylamphetamine is at RN position, hence the name N-ethylamphetamine.
  3. ↑ Ethylamphetamine is structurally similar to N-methylamphetamine (methamphetamine), the ethyl group being replaced in methamphetamine with a methyl group.

References

  1. ↑ "L'éthylamphétamine dans le traitement de l'obésité". Praxis 45 (43): 986–988. October 1956. PMID 13389142. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  3. ↑ 3.0 3.1 3.2 "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. PMID 38154512. 
  4. ↑ 4.0 4.1 4.2 Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/. "FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]" 
  5. ↑ "N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability". Neuropsychopharmacology 42 (10): 1950–1961. September 2017. doi:10.1038/npp.2017.98. PMID 28530234. 
  6. ↑ Sakloth, Farhana (11 December 2015). Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action. VCU Scholars Compass (Thesis). doi:10.25772/AY8R-PW77. Retrieved 24 November 2024.
  7. ↑ Forsyth, Andrea N (22 May 2012). Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  8. ↑ 8.0 8.1 8.2 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  9. ↑ 9.0 9.1 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  10. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. March 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  11. ↑ 11.0 11.1 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). [...]" 
  12. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. April 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  13. ↑ "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  14. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  15. ↑ 15.0 15.1 15.2 "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther 357 (1): 134–144. April 2016. doi:10.1124/jpet.115.229765. PMID 26791601. https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA. 
  16. ↑ "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Mol Pharmacol 60 (6): 1181–1188. December 2001. doi:10.1124/mol.60.6.1181. PMID 11723224. 
  17. ↑ 17.0 17.1 "The effect of N-alkyl chain length of stereochemistry on the absorption, metabolism and during excretion of N-alkylamphetamines in man". J Pharm Pharmacol 25 (10): 793–799. October 1973. doi:10.1111/j.2042-7158.1973.tb09943.x. PMID 4151673. 

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