Chemistry:MMAI

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5-Methoxy-6-methyl-2-aminoindane (MMAI) is a drug of the 2-aminoindane group developed in the 1990s by a team led by David E. Nichols at Purdue University.[1] It acts as a less neurotoxic and highly selective serotonin releasing agent (SSRA) and produces entactogenic effects in humans.[1][2][3][4] The drug has been sold as a designer drug and research chemical online since 2010.

Interactions

Pharmacology

The drug is one of the only known monoamine releasing agents (MRAs) with greater than 100-fold selectivity for the serotonin transporter (SERT) over the dopamine transporter (DAT).[5] Receptor interaction data for MMAI have also been reported.[6][7]

MMAI has been shown to relieve stress-induced depression in rats more robustly than sertraline,[8] and as a result it has been suggested that SSRAs like MMAI and 4-methylthioamphetamine (4-MTA) could be developed as novel antidepressants with a faster onset of therapeutic action and superior effectiveness to current antidepressants such as the selective serotonin reuptake inhibitors (SSRIs).[9]

MMAI alone does not appear to produce serotonergic neurotoxicity with either acute or chronic administration in animals.[10][11] However, subsequent research found that a single high dose of MMAI could produce significant serotonergic neurotoxicity.[10][11] In addition, combination of MMAI with the dopamine releasing agent dextroamphetamine has been found to produce dose-dependent serotonergic neurotoxicity in animals.[10] Hence, MMAI is not a fully non-neurotoxic MDMA analogue.[10][11]

Activities of 2-aminoindanes and amphetamine relatives
Compound Monoamine release (EC50, nM) Ref
Serotonin Norepinephrine Dopamine
2-AI >10,000 86 439 [6]
MDAI 114 117 1,334 [6]
MMAI 31 3,101 >10,000 [6]
MEAI 134 861 2,646 [6]
d-Amphetamine 698–1,765 6.6–7.2 5.8–24.8 [12][13][14][15][16]
MDA 160–162 47–108 106–190 [17][14][18]
MDMA 50–85 54–110 51–278 [12][19][20][17][18]
3-MA ND 58.0 103 [14]
Notes: The smaller the value, the more strongly the compound produces the effect. 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: [6]

Chemistry

MMAI is the 2-aminoindane analogue of 3-methoxy-4-methylamphetamine (MMA).[21][3]

See also

  • Substituted 2-aminoindane
  • Cyclized phenethylamine

References

  1. ↑ 1.0 1.1 "Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan". European Journal of Pharmacology 258 (1–2): 1–13. June 1994. doi:10.1016/0014-2999(94)90051-5. PMID 7925587. 
  2. ↑ "Neuroendocrine pharmacology of three serotonin releasers: 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAi) and p-methylthioamphetamine (MTA)". The Journal of Pharmacology and Experimental Therapeutics 279 (3): 1261–1267. December 1996. doi:10.1016/S0022-3565(25)21285-X. PMID 8968349. 
  3. ↑ 3.0 3.1 "Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters". Molecular Pharmacology 43 (2): 271–276. February 1993. doi:10.1016/S0026-895X(25)13609-2. PMID 8429828. 
  4. ↑ "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. https://edoc.unibas.ch/57357/1/20170920120908_59c23e44b5f0e.pdf. 
  5. ↑ "Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics". Exp Neurol 343. September 2021. doi:10.1016/j.expneurol.2021.113778. PMID 34090893. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl) 236 (3): 989–999. March 2019. doi:10.1007/s00213-019-05207-1. PMID 30904940. 
  7. ↑ "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. 
  8. ↑ "The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats". Stress 2 (2): 91–100. December 1997. doi:10.3109/10253899709014740. PMID 9787258. 
  9. ↑ "Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action". Neuropharmacology 38 (7): 1055–1061. July 1999. doi:10.1016/S0028-3908(99)00023-4. PMID 10428424. 
  10. ↑ 10.0 10.1 10.2 10.3 "Combined administration of a non-neurotoxic 3,4-methylenedioxymethamphetamine analogue with amphetamine produces serotonin neurotoxicity in rats". Neuropharmacology 30 (7): 819–822. July 1991. doi:10.1016/0028-3908(91)90192-e. PMID 1717873. 
  11. ↑ 11.0 11.1 11.2 "[3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues". Eur J Pharmacol 200 (1): 9–16. July 1991. doi:10.1016/0014-2999(91)90659-e. PMID 1685125. 
  12. ↑ 12.0 12.1 "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. 
  13. ↑ "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. 
  14. ↑ 14.0 14.1 14.2 "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. 
  15. ↑ "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. 
  16. ↑ "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). [...]" 
  17. ↑ 17.0 17.1 "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. ↑ 18.0 18.1 "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. ↑ "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. 
  20. ↑ "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. 
  21. ↑ "Novel serotonergic agents". Drug des Discov 9 (3–4): 299–312. 1993. PMID 8400010. https://bitnest.netfirms.com/external/DrugDes.Disc/9.299. 



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