Chemistry:18-Methoxycoronaridine
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| Routes of administration | Oral |
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| Formula | C22H28N2O3 |
| Molar mass | 368.477 g·mol−1 |
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18-Methoxycoronaridine (18-MC, or MM-110), also known as zolunicant, is a derivative of ibogaine invented in 1996 by the research team around the pharmacologist Stanley D. Glick from the Albany Medical College and the chemists Upul K. Bandarage and Martin E. Kuehne from the University of Vermont. In animal studies it has proved to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine and sucrose.[1][2] It has also been shown to produce anorectic effects in obese rats, most likely due to the same actions on the reward system which underlie its anti-addictive effects against drug addiction.[3]
18-MC was in the early stages of human testing by the California-based drug development company Savant HWP before being acquired by MindMed, a Canadian pharmaceutical company newly listed on the NASDAQ in April 2021.[4][5] In 2002 the research team began raising funds for human trials, but were unable to secure the estimated $5 million needed.[6] In 2010, Obiter Research, a chemical manufacturer in Champaign, Illinois, signed a patent license with Albany Medical College and the University of Vermont, allowing them the right to synthesize and market 18-MC and other congeners. In 2012 the National Institute on Drug Abuse gave a $6.5 million grant to Savant HWP for human trials.[5] In 2017 it went into Phase-II trials in Brazil for treatment of Leishmaniasis at the Evandro Chagas Institute,[7] but not for approval for use as a treatment for drug addiction. A phase 2a study of MM-110 treatment in patients experiencing opioid withdrawal is set to commence in Q2 2022.[8]
Pharmacology
18-MC is a α3β4 nicotinic antagonist and, in contrast to ibogaine, has no affinity at the α4β2 subtype nor at NMDA-channels nor at the serotonin transporter,[9] and has significantly reduced affinity for sodium channels and for the σ receptor, but retains modest affinity for μ-opioid receptors where it acts as an agonist,[10] and κ-opioid receptors.[11] The sites of action in the brain include the medial habenula, interpeduncular nucleus,[12][13][14] dorsolateral tegmentum and basolateral amygdala.[15] (±)-18-MC competitively inhibits α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly blocks CaV2.2.[16]
Chemistry
Derivatives
A number of derivatives of 18-MC have been developed, with several of them being superior to 18-MC itself, the methoxyethyl congener ME-18-MC being more potent than 18-MC with similar efficacy, and the methylamino analogue 18-MAC being more effective than 18-MC with around the same potency. These compounds were also found to act as selective α3β4 nicotinic acetylcholine antagonists, with little or no effect on NMDA receptors.[17][18]
See also
References
- ↑ "18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats". Brain Research 719 (1–2): 29–35. May 1996. doi:10.1016/0006-8993(96)00056-X. PMID 8782860.
- ↑ "Brain regions mediating alpha3beta4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration". European Journal of Pharmacology 599 (1–3): 91–5. December 2008. doi:10.1016/j.ejphar.2008.09.038. PMID 18930043.
- ↑ "18-methoxycoronaridine: a potential new treatment for obesity in rats?". Psychopharmacology 201 (3): 339–50. December 2008. doi:10.1007/s00213-008-1290-9. PMID 18751969.
- ↑ Mindmed Acquires Opioid Addiction Drug Candidate Based on the Natural Psychedelic Ibogaine newswire.ca September 16, 2019.
- ↑ 5.0 5.1 Albany Med scientist closer to addiction drug success timesunion.com June 27, 2014.
- ↑ Addiction Treatment Strives for Legitimacy. Journal of the American Medical Association. 2002; 288: 3096-3101.
- ↑ "Phase 2 Trial to Evaluate 18-Methoxycoronaridine Efficacy, Safety and Tolerability in Cutaneous Leishmaniasis Patients". https://clinicaltrials.gov/ct2/show/NCT03084952.
- ↑ "Opioid Use Disorder: Zolunicant's Potential for Unmet Treatment Needs". MindMed.co. 20 May 2022. https://mindmed.co/news/video/opioid-use-disorder-zolunicants-potential-for-unmet-treatment-needs/.
- ↑ "Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment". Pharmacology, Biochemistry, and Behavior 75 (3): 607–18. June 2003. doi:10.1016/S0091-3057(03)00119-9. PMID 12895678.
- ↑ "Effect of Iboga alkaloids on μ-opioid receptor-coupled G protein activation". PLOS ONE 8 (10): e77262. 2013. doi:10.1371/journal.pone.0077262. PMID 24204784. Bibcode: 2013PLoSO...877262A.
- ↑ Glick SD, Maisonneuve IM, Hough LB, Kuehne ME, Bandarage UK. (±)-18-Methoxycoronaridine: A Novel Iboga Alkaloid Congener Having Potential Anti-Addictive Efficacy. CNS Drug Reviews 1999;5(1):27-42.
- ↑ "18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats". European Journal of Pharmacology 537 (1–3): 94–8. May 2006. doi:10.1016/j.ejphar.2006.03.045. PMID 16626688.
- ↑ "18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens". Synapse 61 (7): 547–60. July 2007. doi:10.1002/syn.20396. PMID 17447255.
- ↑ "Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats". Neuropharmacology 53 (1): 18–26. July 2007. doi:10.1016/j.neuropharm.2007.04.010. PMID 17544456.
- ↑ "Brain regions mediating alpha3beta4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration". European Journal of Pharmacology 599 (1–3): 91–5. December 2008. doi:10.1016/j.ejphar.2008.09.038. PMID 18930043.
- ↑ "Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and CaV2.2 channels". Neuropharmacology 175: 108194. September 2020. doi:10.1016/j.neuropharm.2020.108194. PMID 32540451. https://ro.uow.edu.au/ihmri/1536.
- ↑ "Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents". Journal of Medicinal Chemistry 46 (13): 2716–30. June 2003. doi:10.1021/jm020562o. PMID 12801235.
- ↑ "Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration". European Journal of Pharmacology 492 (2–3): 159–67. May 2004. doi:10.1016/j.ejphar.2004.03.062. PMID 15178360.
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