Chemistry:4-Methylamphetamine

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4-Methylamphetamine (4-MA), also known by the former proposed brand name Aptrol, is a stimulant and anorectic drug of the amphetamine family. It is structurally related to mephedrone (4-methylmethcathinone).

Pharmacology

In vitro, 4-methylamphetamine acts as a potent and well-balanced serotonin, norepinephrine, and dopamine releasing agent (SNDRA) with EC50 values of 53.4 nM, 22.2 nM, and 44.1 nM at the serotonin, norepinephrine, and dopamine transporters, respectively.[1] Receptor interaction data for 4-methylamphetamine have also been reported.[2]

However, more recent in vivo studies that involved performing microdialysis on rats showed a different trend. These studies showed that 4-methylamphetamine is much more potent at elevating serotonin (~18 x baseline) relative to dopamine (~5 x baseline). The authors speculated that this is because 5-HT release dampens DA release through some mechanism. For example, it was suggested that a possible cause for this could be activation of 5HT2C receptors since this is known to inhibit DA release. In addition there are alternative explanations such as 5-HT release then going on to encourage GABA release, which has an inhibitory effect on DA neurons.[3]

Monoamine release of 4-methylamphetamine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Dextroamphetamine 6.6–10.2 5.8–24.8 698–1,765 [4][5][6][7]
Dextromethamphetamine 12.3–14.3 8.5–40.4 736–1,292 [4][8][6][7]
4-Methylamphetamine 22.2 44.1 53.4 [1][9][6]
4-Methylmethamphetamine (mephedrine) 66.9 41.3 67.4 [10][11]
4-Methylcathinone (normephedrone) 100 220 210 [12][13][14]
4-Methylmethcathinone (mephedrone) 58–62.7 49.1–51 118.3–122 [8][5][15][16][17]
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: [18][19]

Research

4-MA was investigated as an appetite suppressant in 1952 and was even given a trade name, Aptrol, but development was apparently never completed.[20] More recently it has been reported as a novel designer drug.

In animal studies, 4-MA was shown to have the lowest rate of self-administration out of a range of similar drugs tested (the others being 3-methylamphetamine, 4-fluoroamphetamine, and 3-fluoroamphetamine), likely as a result of having the highest potency for releasing serotonin relative to dopamine.[1][21]

Society and culture

More than a dozen deaths were reported throughout Europe in 2012-2013 after consumption of amphetamine ('speed') contaminated with 4-methylamphetamine.[22][23][24]

See also

References

  1. ↑ 1.0 1.1 1.2 "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics 313 (2): 848–854. May 2005. doi:10.1124/jpet.104.080101. PMID 15677348. 
  2. ↑ "Pharmacological profile of mephedrone analogs and related new psychoactive substances". Neuropharmacology 134 (Pt A): 4–12. May 2018. doi:10.1016/j.neuropharm.2017.07.026. PMID 28755886. 
  3. ↑ "Role of serotonin in central dopamine dysfunction". CNS Neuroscience & Therapeutics 16 (3): 179–194. June 2010. doi:10.1111/j.1755-5949.2010.00135.x. PMID 20557570. 
  4. ↑ 4.0 4.1 "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. 
  5. ↑ 5.0 5.1 "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. 
  6. ↑ 6.0 6.1 6.2 "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. 
  7. ↑ 7.0 7.1 "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). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays." 
  8. ↑ 8.0 8.1 "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. 
  9. ↑ 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. 
  10. ↑ "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. 
  11. ↑ 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.
  12. ↑ "Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters". Br J Pharmacol 173 (17): 2657–2668. September 2016. doi:10.1111/bph.13547. PMID 27391165. 
  13. ↑ "Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats". Eur Neuropsychopharmacol 26 (2): 288–297. February 2016. doi:10.1016/j.euroneuro.2015.12.010. PMID 26738428. 
  14. ↑ "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. 32. 2017. pp. 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. 
  15. ↑ "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology 236 (3): 915–924. March 2019. doi:10.1007/s00213-018-5063-9. PMID 30341459. 
  16. ↑ "Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents". ACS Chem Neurosci 10 (1): 740–745. January 2019. doi:10.1021/acschemneuro.8b00524. PMID 30354055. 
  17. ↑ "Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues". Br J Pharmacol 172 (10): 2433–2444. May 2015. doi:10.1111/bph.13030. PMID 25438806. 
  18. ↑ "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. 
  19. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  20. ↑ "2-Amino-1-(p-methylphenyl)-propane (aptrol) as an anorexigenic agent in weight reduction". New York State Journal of Medicine 52 (2): 223–226. January 1952. PMID 14890975. 
  21. ↑ "In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat". The Journal of Pharmacology and Experimental Therapeutics 337 (1): 218–225. April 2011. doi:10.1124/jpet.110.176271. PMID 21228061. 
  22. ↑ "4-Methyl-amphetamine: a health threat for recreational amphetamine users". Journal of Psychopharmacology 27 (9): 817–822. September 2013. doi:10.1177/0269881113487950. PMID 23784740. 
  23. ↑ "4-Methyl-amphetamine: A health threat for recreational amphetamine users". ResearchGate. https://www.researchgate.net/publication/240306373. 
  24. ↑ "4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug". Mini Reviews in Medicinal Chemistry 13 (14): 2097–2101. December 2013. doi:10.2174/13895575113136660106. PMID 24195663. 



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