Chemistry:MEAI

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MEAI, also known as 5-methoxy-2-aminoindane (5-MeO-AI), is a monoamine releasing agent of the 2-aminoindane group.[1] It specifically acts as a selective serotonin releasing agent (SSRA).[1] The drug is under development for the treatment of alcoholism, cocaine use disorder, metabolic syndrome, and obesity under the developmental code name CMND-100.[2]

Use and effects

When used recreationally, MEAI is reported to produce mild psychoactive effects and euphoria.[1]

Interactions

Pharmacology

Pharmacodynamics

MEAI is a monoamine releasing agent (MRA).[1] It is a modestly selective serotonin releasing agent (SSRA), with 6-fold preference for induction of serotonin release over norepinephrine release and 20-fold preference for induction of serotonin release over dopamine release.[1] In addition to inducing monoamine neurotransmitter release, MEAI has moderate affinity for the α2-adrenergic receptor.[1] Based on these findings, MEAI might produce MDMA-like entactogenic and sympathomimetic effects but may be expected to have reduced misuse liability in comparison.[1]

Activities of 2-aminoindanes and amphetamine relatives
Compound Monoamine release (EC50, nM) Ref
Serotonin Norepinephrine Dopamine
2-AI >10,000 86 439 [1]
MDAI 114 117 1,334 [1]
MMAI 31 3,101 >10,000 [1]
MEAI 134 861 2,646 [1]
d-Amphetamine 698–1,765 6.6–7.2 5.8–24.8 [3][4][5][6][7]
MDA 160–162 47–108 106–190 [8][5][9]
MDMA 50–85 54–110 51–278 [3][10][11][8][9]
3-MA ND 58.0 103 [5]
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: [1]

Chemistry

MEAI, also known as 5-methoxy-2-aminoindane, is a 2-aminoindane derivative.[12] It is the 2-aminoindane analogue of the amphetamine 3-methoxyamphetamine.[12]

History

MEAI appears to have been first synthesized in 1956.[1] Its molecular structure was first mentioned implicitly in a markush structure schema appearing in a patent from 1998.[13] It was later explicitly and pharmacologically described in a peer reviewed paper in 2017 by David Nutt and Ezekiel Golan et al.[14] followed by another in February 2018 which detailed the pharmacokinetics, pharmacodynamics and metabolism of MEAI by Shimshoni, David Nutt, Ezekiel Golan et al.[15] One year later it was studied and reported on in another peer reviewed paper by Halberstadt et al.[16] The aminoindane family of molecules was, perhaps, first chemically described in 1980.[17][18]

Research

Alcohol substitute

MEAI was an early candidate of alcohol replacement drugs that came to market during a late 2010s movement to replace alcohol with less-toxic alternatives spearheaded by British psychopharmacologist David Nutt[19][20][21] rippling to the rest of Europe.[22]

In an act of gonzo journalism, Michael Slezak writing for New Scientist, tried and reported on his experience with MEAI[23] after being provided with it by Dr Zee (Ezekiel Golan)[24] following an interview.[23] Golan claimed that he invented MEAI and originally intended for it to be sold as a legal high but changed his mind, indicating plans to work with Nutt and his company DrugScience. The goal was to develop MEAI further based on Golan's patents as a "binge behaviour regulator"[25] and "alcoholic beverage substitute".[26]

In 2018, a company named Diet Alcohol Corporation of the Americas (DACOA) began openly marketing an MEAI-based drink called "Pace" for sale in the USA and Canada. Pace was described as a 50ml bottle containing 160 mg of MEAI in mineral water. Distribution halted after Health Canada released a warning indicating the substance was considered illegal to market for consumption in Canada due to structural similarity to amphetamine.[27][28] In a December 2018 article by CBC News, Dr Zee (Ezekiel Golan) was interviewed and publicly came out as the "lead scientist" of Pace claiming "tens of thousands" of bottles were already sold in Canada.[29] Golan claimed the MEAI featured in Pace was "manufactured in India" and "bottled in Delaware".[29] Health Canada provided a statement to CBC News stating "Pace is an illegal and unauthorized product in Canada."

Clinical development

On May 26, 2022, MEAI was prepared for FDA registration by Clearmind Medicine Inc.;[30][31][32] Clearmind Medicine claims wide intellectual property holdings to Ezekiel Golan's patents.[33][34][35][36] In March 2022 Clearmind Medicine announced supportive evidence from animal studies in mice attesting to suppression of alcohol consumption.[37] In June 2022 Clearmind Medicine announced promising results from animal studies that showed promise for treating cocaine addiction with MEAI.[38][39]

MEAI, under the developmental code name CMND-100, is under development by Clearmind Medicine for the treatment of alcoholism, cocaine use disorder, metabolic syndrome, and obesity.[2] As of October 2024, it is in the preclinical stage of development for these indications.[2]

See also

  • Substituted 2-aminoindane
  • Cyclized phenethylamine

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "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. 
  2. ↑ 2.0 2.1 2.2 "Revolutionary Psychedelics for Treating Addiction & Mental Health". 16 December 2024. https://www.clearmindmedicine.com/news-release/clearmind-medicine-announces-irb-approval-for-fda-first-in-human-clinical-trial-of-cmnd-100-at-second-clinical-site. 
  3. ↑ 3.0 3.1 "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. 
  4. ↑ "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. 
  5. ↑ 5.0 5.1 5.2 "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. 
  6. ↑ "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. 
  7. ↑ "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). [...]" 
  8. ↑ 8.0 8.1 "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. 
  9. ↑ 9.0 9.1 "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. 
  10. ↑ "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. 
  11. ↑ "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. 
  12. ↑ 12.0 12.1 "Novel serotonergic agents". Drug des Discov 9 (3–4): 299–312. 1993. PMID 8400010. https://bitnest.netfirms.com/external/DrugDes.Disc/9.299. 
  13. ↑ Haadsma-Svensson SR, Andersson BR, Sonesson CA, Lin CH, Waters RN, Svensson KA, Carlsson PA, Hansson LO, Stjernlof NP, "2-aminoindans as selective dopamine D3 ligands", US patent 5708018, published 1998-01-13, assigned to Pharmacia & Upjohn Co.
  14. ↑ "Toxicological evaluation of 5-methoxy-2-aminoindane (MEAI): Binge mitigating agent in development". Toxicology and Applied Pharmacology 319: 59–68. March 2017. doi:10.1016/j.taap.2017.01.018. PMID 28167221. Bibcode: 2017ToxAP.319...59S. 
  15. ↑ "Pharmacokinetic and pharmacodynamic evaluation of 5-methoxy-2-aminoindane (MEAI): A new binge-mitigating agent". Toxicology and Applied Pharmacology 343: 29–39. March 2018. doi:10.1016/j.taap.2018.02.009. PMID 29458138. Bibcode: 2018ToxAP.343...29S. 
  16. ↑ "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology 236 (3): 989–999. March 2019. doi:10.1007/s00213-019-05207-1. PMID 30904940. 
  17. ↑ "Aminoindanes--the next wave of 'legal highs'?". Drug Testing and Analysis 3 (7–8): 479–482. 2011. doi:10.1002/dta.318. PMID 21748859. 
  18. ↑ "Comparison of biological effects of N-alkylated congeners of beta-phenethylamine derived from 2-aminotetralin, 2-aminoindan, and 6-aminobenzocycloheptene". Journal of Medicinal Chemistry 23 (7): 745–749. July 1980. doi:10.1021/jm00181a009. PMID 7190613. 
  19. ↑ "Decision making about illegal drugs: time for science to take the lead" (in en). Nobel Forum, Karolinska Institutet. 23 October 2013. https://www.youtube.com/watch?v=mDo09IBVHZw. 
  20. ↑ "Drug harms in the UK: a multicriteria decision analysis". Lancet (London, England) 376 (9752): 1558–65. November 2010. doi:10.1016/S0140-6736(10)61462-6. PMID 21036393. 
  21. ↑ "Hangover free alcohol is finally here" (in en). The Independent. 24 September 2016. https://www.independent.co.uk/life-style/health-and-families/health-news/hangover-free-alcohol-david-nutt-alcosynth-nhs-postive-effects-benzodiazepine-guy-bentley-a7324076.html. 
  22. ↑ "Rauschmittel und gesellschaftliche Probleme" (in de-DE). 29 April 2019. https://benedictwermter.com/gesellschaftliche-probleme-und-rauschmittel-drug-related-societal-issues/. 
  23. ↑ 23.0 23.1 "High and dry? Party drug could target excess drinking" (in en-US). 30 December 2014. https://www.newscientist.com/article/mg22530022-900-high-and-dry-party-drug-could-target-excess-drinking/. 
  24. ↑ "An Interview with Dr Z". New Scientist: pp. 1–3. 9 August 2014. https://www.drzee.org/_files/ugd/7ca39c_857476e79f6947d3befecdd31deaa83f.pdf. 
  25. ↑ Golan E, "Binge behavior regulators", US patent 10406123B2, issued 2019-09-10
  26. ↑ Golan E, "Alcoholic beverage substitutes", US patent 20170360067, issued 2017-12-21
  27. ↑ "Advisory - Health Canada warns consumers that Pace, promoted as an alcohol substitute, is unauthorized and may pose serious health risks". Health Canada. 21 December 2018. https://www.newswire.ca/news-releases/advisory---health-canada-warns-consumers-that-pace-promoted-as-an-alcohol-substitute--is-unauthorized-and-may-pose-serious-health-risks-703346102.html. 
  28. ↑ "FACT CHECK: Is Pace, an "Alcohol Alternative," Legal in Canada?". The Walrus. Toronto, Ontario. 24 April 2019. https://www.thewalrus-factchecking.com/post/fact-check-is-pace-an-alcohol-alternative-legal-in-canada. 
  29. ↑ 29.0 29.1 "Is this drink really a new 'alcohol alternative'?". Information Morning Saint John: pp. All. 8 December 2018. https://www.cbc.ca/news/canada/new-brunswick/pace-drink-alcohol-alternative-binge-drinking-canada-1.4933533. 
  30. ↑ "Clearmind Medicine". https://www.clearmindmedicine.com/news-release/clearmind-announces-successful-pre-ind-meeting-with-u-s-fda-for-cmnd-100-for-alcohol-use-disorder. 
  31. ↑ "Clearmind Medicine Inc.". CSE:CMND. https://www.thecse.com/en/listings/life-sciences/clearmind-medicine-inc. 
  32. ↑ וינרב, גלי (16 February 2022). "החברה שמנסה להפוך סם פסיכדלי למוצר נגד התמכרות" (in Hebrew). Globes. https://www.globes.co.il/news/article.aspx?did=1001402418. 
  33. ↑ Golan E, "Binge behavior regulators", US patent 10137096, published 2018-11-27
  34. ↑ Golan E, "Alcoholic beverage substitutes", EP patent 3230256, published 2019-11-13
  35. ↑ Golan E, "Binge behavior regulators", EP patent 3230255, published 2017-10-18
  36. ↑ "The Science and IP Behind our Treatments". Clearmind. https://www.clearmindmedicine.com/science-and-ip. 
  37. ↑ "Clearmind Medicine". https://www.clearmindmedicine.com/news-release/clearmind-medicine-announces-positive-results-on-cmnd-100-trials. 
  38. ↑ "Clearmind Medicine". https://www.clearmindmedicine.com/news-release/clearmind-medicine-announces-positive-pre-clinical-results-for-cocaine-addiction-treatment. 
  39. ↑ "Clearmind Medicine". https://www.clearmindmedicine.com/news-release/clearmind-medicine-announces-additional-positive-pre-clinical-results-for-its-cocaine-addiction-treatment. 



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