Chemistry:4-Methylcathinone

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4-Methylcathinone (4-MC), also known as normephedrone is a stimulant drug of the cathinone group. It is an active metabolite of the better known drug mephedrone (4-methylmethcathinone or 4-MMC).[1][2][3][4]

4-MC is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) similarly to mephedrone.[5][6][7] It displays a 2.4-fold selectivity to promote monoamine release via DAT over SERT as opposed to 309-fold selectivity for cathinone.[6] It also releases norepinephrine.[6]

Monoamine release of 4-methylcathinone and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [8][9]
Dextromethamphetamine 12.3–13.8 8.5–24.5 736–1,292 [8][10]
4-Methylamphetamine 22.2 44.1 53.4 [11][12][13]
4-Methylmethamphetamine 66.9 41.3 67.4 [14][15]
MDMA 54.1–110 51.2–278 49.6–72 [8][10][16][17][13][18]
Cathinone 23.6–25.6 34.8–83.1 6,100–7,595 [13][19][20]
Methcathinone 22–26.1 12.5–49.9 2,592–5,853 [13][19][21][22][20]
Normephedrone 100 220 210 [5][6][7]
  R(+)-Normephedrone 89 150 179 [7][6]
  S(–)-Normephedrone 115 391 1,592 [7][6]
Mephedrone 58–62.7 49.1–51 118.3–122 [10][9][19][22][23]
  S(–)-Mephedrone ND 74 61 [7][24]
  R(+)-Mephedrone ND 31 1,470 [7][24]
Methylone 140–270 117–220 234–708 [10][9][15][25][26]
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: [27][28]

See also

References

  1. ↑ "nor-Mephedrone". Cayman Chemical. https://www.caymanchem.com/app/template/Product.vm/catalog/9000940. 
  2. ↑ "Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry". Analytical and Bioanalytical Chemistry 397 (3): 1225–33. June 2010. doi:10.1007/s00216-010-3636-5. PMID 20333362. 
  3. ↑ "In vitro metabolism studies on mephedrone and analysis of forensic cases". Drug Testing and Analysis 5 (6): 430–8. June 2013. doi:10.1002/dta.1369. PMID 22573603. 
  4. ↑ "The pharmacology and toxicology of the synthetic cathinone mephedrone (4-methylmethcathinone)". Drug Testing and Analysis 3 (7–8): 454–63. July–August 2011. doi:10.1002/dta.312. PMID 21755604. 
  5. ↑ 5.0 5.1 "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. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "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. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. 32. Springer. 2017. pp. 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. 
  8. ↑ 8.0 8.1 8.2 "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. 
  9. ↑ 9.0 9.1 9.2 "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  10. ↑ 10.0 10.1 10.2 10.3 "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  11. ↑ "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. 
  12. ↑ Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. 22 May 2012. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  13. ↑ 13.0 13.1 13.2 13.3 "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. 
  14. ↑ "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. 
  15. ↑ 15.0 15.1 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.
  16. ↑ "The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue". Neuropharmacology 101: 68–75. February 2016. doi:10.1016/j.neuropharm.2015.09.004. PMID 26362361. 
  17. ↑ "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–1229. June 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. 
  18. ↑ "The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats". Psychopharmacology (Berl) 237 (12): 3703–3714. December 2020. doi:10.1007/s00213-020-05648-z. PMID 32875347. 
  19. ↑ 19.0 19.1 19.2 "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. 
  20. ↑ 20.0 20.1 "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. 
  21. ↑ Shalabi, Abdelrahman R. (14 December 2017). Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters. VCU Scholars Compass (Thesis). doi:10.25772/M4E1-3549. Retrieved 24 November 2024.
  22. ↑ 22.0 22.1 "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. 
  23. ↑ "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. 
  24. ↑ 24.0 24.1 "Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats". Br J Pharmacol 172 (3): 883–894. February 2015. doi:10.1111/bph.12951. PMID 25255824. 
  25. ↑ "Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation". ACS Chem Neurosci 12 (7): 1170–1177. April 2021. doi:10.1021/acschemneuro.0c00797. PMID 33689284. 
  26. ↑ "Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats". Neuropsychopharmacology 42 (3): 649–660. February 2017. doi:10.1038/npp.2016.213. PMID 27658484. 
  27. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  28. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 



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