4-Methylcathinone Explained

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. It displays a 2.4-fold selectivity to promote monoamine release via DAT over SERT as opposed to 309-fold selectivity for cathinone. It also releases norepinephrine.

Compound data-sort-type="number" !data-sort-type="number" !data-sort-type="number" !Ref
6.6–7.2 5.8–24.8 698–1,765 [5] [6]
12.3–13.8 8.5–24.5 736–1,292 [7]
22.2 44.1 53.4 [8] [9] [10]
66.9 41.3 67.4 [11] [12]
54.1–110 51.2–278 49.6–72 [13] [14] [15]
23.6–25.6 34.8–83.1 6,100–7,595 [16] [17]
22–26.1 12.5–49.9 2,592–5,853 [18] [19]
100 220 210 [20] [21] [22]
R(+)-Normephedrone 89 150 179
S(–)-Normephedrone 115 391 1,592
58–62.7 49.1–51 118.3–122 [23]
S(–)-Mephedrone 74 61 [24]
R(+)-Mephedrone 31 1,470
140–270 117–220 234–708 [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

Notes and References

  1. Web site: nor-Mephedrone . Cayman Chemical . 27 June 2015.
  2. Meyer MR, Wilhelm J, Peters FT, Maurer HH . 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 . 20333362 . 10.1007/s00216-010-3636-5 . 21471611 .
  3. Pedersen AJ, Reitzel LA, Johansen SS, Linnet K . In vitro metabolism studies on mephedrone and analysis of forensic cases . Drug Testing and Analysis . 5 . 6 . 430–8 . June 2013 . 22573603 . 10.1002/dta.1369 .
  4. Dargan PI, Sedefov R, Gallegos A, Wood DM . The pharmacology and toxicology of the synthetic cathinone mephedrone (4-methylmethcathinone) . Drug Testing and Analysis . 3 . 7–8 . 454–63 . July–August 2011 . 21755604 . 10.1002/dta.312 .
  5. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS . Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin . Synapse . 39 . 1 . 32–41 . January 2001 . 11071707 . 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 .
  6. Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW . Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products . Neuropsychopharmacology . 38 . 4 . 552–562 . 2013 . 23072836 . 3572453 . 10.1038/npp.2012.204 .
  7. Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV . The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue . Neuropsychopharmacology . 37 . 5 . 1192–1203 . 2012 . 22169943 . 3306880 . 10.1038/npp.2011.304 .
  8. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL . 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 . 15677348 . 10.1124/jpet.104.080101 . 12135483 .
  9. Forsyth AN . Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines . ScholarWorks@UNO . 22 May 2012 . 4 November 2024.
  10. Book: Blough B . Dopamine-releasing agents . Trudell ML, Izenwasser S . Dopamine Transporters: Chemistry, Biology and Pharmacology . 305–320 . July 2008 . 978-0-470-11790-3 . 181862653 . OL18589888W . Wiley . Hoboken [NJ] . https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf .
  11. Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH . N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability . Neuropsychopharmacology . 42 . 10 . 1950–1961 . September 2017 . 28530234 . 5561352 . 10.1038/npp.2017.98 .
  12. Sakloth . Farhana . Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action . VCU Scholars Compass . 11 December 2015 . 10.25772/AY8R-PW77 . 24 November 2024.
  13. Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, Baumann MH . 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 . 26362361 . 4681602 . 10.1016/j.neuropharm.2015.09.004 .
  14. Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL . 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 . 12761331 . 10.1124/mol.63.6.1223 . 839426 .
  15. Brandt SD, Walters HM, Partilla JS, Blough BE, Kavanagh PV, Baumann MH . 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 . 32875347 . 10.1007/s00213-020-05648-z . 7686291 .
  16. Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB . 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 . 30341459 . 6475490 . 10.1007/s00213-018-5063-9 .
  17. Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE . Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones . Neuropharmacology . 245 . 109827 . March 2024 . 38154512 . 10.1016/j.neuropharm.2023.109827 . 10842458 . March 1, 2025 .
  18. Shalabi . Abdelrahman R. . Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters . VCU Scholars Compass . 14 December 2017 . 10.25772/M4E1-3549 . 24 November 2024.
  19. Walther D, Shalabi AR, Baumann MH, Glennon RA . 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 . 30354055 . 8269283 . 10.1021/acschemneuro.8b00524 .
  20. Mayer FP, Wimmer L, Dillon-Carter O, Partilla JS, Burchardt NV, Mihovilovic MD, Baumann MH, Sitte HH . Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters . Br J Pharmacol . 173 . 17 . 2657–2668 . September 2016 . 27391165 . 4978154 . 10.1111/bph.13547 .
  21. Hutsell BA, Baumann MH, Partilla JS, Banks ML, Vekariya R, Glennon RA, Negus SS . Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats . Eur Neuropsychopharmacol . 26 . 2 . 288–297 . February 2016 . 26738428 . 5331761 . 10.1016/j.euroneuro.2015.12.010 .
  22. Glennon RA, Dukat M . Structure-Activity Relationships of Synthetic Cathinones . Curr Top Behav Neurosci . Current Topics in Behavioral Neurosciences . 32 . 19–47 . 2017 . 27830576 . 5818155 . 10.1007/7854_2016_41 . 978-3-319-52442-9 .
  23. Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS . Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues . Br J Pharmacol . 172 . 10 . 2433–2444 . May 2015 . 25438806 . 4409897 . 10.1111/bph.13030 .
  24. Gregg RA, Baumann MH, Partilla JS, Bonano JS, Vouga A, Tallarida CS, Velvadapu V, Smith GR, Peet MM, Reitz AB, Negus SS, Rawls SM . Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats . Br J Pharmacol . 172 . 3 . 883–894 . February 2015 . 25255824 . 4301696 . 10.1111/bph.12951 .
  25. Glatfelter GC, Walther D, Evans-Brown M, Baumann MH . Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation . ACS Chem Neurosci . 12 . 7 . 1170–1177 . April 2021 . 33689284 . 9423000 . 10.1021/acschemneuro.0c00797 .
  26. Elmore JS, Dillon-Carter O, Partilla JS, Ellefsen KN, Concheiro M, Suzuki M, Rice KC, Huestis MA, Baumann MH . Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats . Neuropsychopharmacology . 42 . 3 . 649–660 . February 2017 . 27658484 . 5240186 . 10.1038/npp.2016.213 .
  27. Rothman RB, Baumann MH . Monoamine transporters and psychostimulant drugs . Eur J Pharmacol . 479 . 1–3 . 23–40 . October 2003 . 14612135 . 10.1016/j.ejphar.2003.08.054 .
  28. Rothman RB, Baumann MH . Therapeutic potential of monoamine transporter substrates . Current Topics in Medicinal Chemistry . 6 . 17 . 1845–1859 . 2006 . 17017961 . 10.2174/156802606778249766 .

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