Chemistry:4-Methylmethamphetamine

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4-Methylmethamphetamine (4-MMA), also known as mephedrine, is a putative stimulant and entactogen drug of the amphetamine family. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).[1][2] The drug is the β-deketo analogue of mephedrone (4-methylmethcathinone; 4-MMC) and the N-methyl analogue of 4-methylamphetamine (4-MA).[3][4]

Pharmacology

Pharmacodynamics

4-MMA acts as a potent and well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA).[1][2] It induces hyperlocomotion and stereotypy (psychostimulant-like effects) as well as hyperthermia in mice, similarly to methcathinone.[5][6]

Monoamine release of 4-methylmethamphetamine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Dextroamphetamine 6.6–10.2 5.8–24.8 698–1,765 [7][8][9][10]
Dextromethamphetamine 12.3–14.3 8.5–40.4 736–1,292 [7][11][9][10]
4-Methylamphetamine 22.2 44.1 53.4 [12][13][9]
4-Methylmethamphetamine (mephedrine) 66.9 41.3 67.4 [1][2]
4-Methylethylamphetamine 182 550 102 [1]
4-Methylpropylamphetamine 752 IA 650 [1]
4-Methylbutylamphetamine IA IA IA [1]
4-Methylmethcathinone (mephedrone) 58–62.7 49.1–51 118.3–122 [11][8][14][15][16]
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: [17][18]

Dopaminergic neurotoxicity

In contrast to methamphetamine and methcathinone, 4-MMA appears to produce minimal dopaminergic neurotoxicity in mice.[5][6] Conversely, mephedrone shows no dopaminergic neurotoxicity at all in mice.[5][6] It was theorized that 4-methyl and β-keto substitutions on amphetamines may result in loss of activity at the vesicular monoamine transporter 2 (VMAT2), loss of elevations of cytosolic dopamine concentrations, and consequent loss of dopaminergic neurotoxic potential.[5][6] Accordingly, the dopaminergic neurotoxicity of 4-MMA was greatly enhanced by the dopamine precursor levodopa (L-DOPA), the monoamine oxidase inhibitor (MAOI) pargyline, and methamphetamine (a VMAT2 inhibitor/reverser), all of which are known to increase the cytosolic pool of dopamine.[6] However, in contrast to 4-MMA, the dopaminergic neurotoxicity of methcathinone was enhanced only by levodopa and of mephedrone was enhanced only by methamphetamine.[6]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "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. 
  2. ↑ 2.0 2.1 2.2 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.
  3. ↑ "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. March 2010. doi:10.1007/s00216-010-3636-5. PMID 20333362. 
  4. ↑ "4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug". Mini Rev Med Chem 13 (14): 2097–2101. December 2013. doi:10.2174/13895575113136660106. PMID 24195663. 
  5. ↑ 5.0 5.1 5.2 5.3 "Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone". J Pharmacol Exp Ther 360 (3): 417–423. March 2017. doi:10.1124/jpet.116.237768. PMID 28039330. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine". Neuropharmacology 134 (Pt A): 46–56. May 2018. doi:10.1016/j.neuropharm.2017.08.033. PMID 28851615. 
  7. ↑ 7.0 7.1 "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. 
  8. ↑ 8.0 8.1 "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. 
  9. ↑ 9.0 9.1 9.2 "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. 
  10. ↑ 10.0 10.1 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates". 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." 
  11. ↑ 11.0 11.1 "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. 
  12. ↑ "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. 
  13. ↑ 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. 
  14. ↑ "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. 
  15. ↑ "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. 
  16. ↑ "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. 
  17. ↑ "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. 
  18. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 

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