18-Methoxycoronaridine

Last updated
18-Methoxycoronaridine
INN: Zolunicant
18-Methoxycoronaridine.svg
18-methoxycoronaridine 3D BS.png
Clinical data
Other names18-MC; Zolunicant; MM-110; MM110
Routes of
administration 		Oral
Legal status
Legal status
Identifiers
  • methyl (1S,15R,17R,18S)-17-(2-methoxyethyl)-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4,6,8-tetraene-1-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H28N2O3
Molar mass 368.477 g·mol−1
3D model (JSmol)
  • COCC[C@H]1C[C@@H]2C[C@@]3([C@H]1N(C2)CCc4c3[nH]c5c4cccc5)C(=O)OC
  • InChI=1S/C22H28N2O3/c1-26-10-8-15-11-14-12-22(21(25)27-2)19-17(7-9-24(13-14)20(15)22)16-5-3-4-6-18(16)23-19/h3-6,14-15,20,23H,7-13H2,1-2H3/t14-,15+,20+,22-/m1/s1 X mark.svgN
  • Key:DTJQBBHYRQYDEG-SVBQBFEESA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

18-Methoxycoronaridine (18-MC; developmental code name MM-110), also known as zolunicant (INN Tooltip International Nonproprietary Name), 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 proven 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]

Contents

18-MC was originally developed by Savant HWP and later acquired by MindMed in 2019 for development as a treatment for opioid use disorder. [4] A Phase 1 trial in healthy volunteers was completed in 2022 with favorable safety and tolerability. [5] Due to strategic reprioritization, MindMed discontinued active development of MM-110 in 2023 and has been seeking non-dilutive funding or partners to potentially restart the program; as of 2025 the program remains shelved. [6] [7] A separate Phase 2 trial in Brazil for cutaneous leishmaniasis (initiated 2017) has unknown status with no published results. [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. [2] (±)-18-MC competitively inhibits α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly blocks CaV2.2. [15]

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. [16] [17] Iboga alkaloids.png

See also

References

  1. ↑ Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH (May 1996). "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. doi:10.1016/0006-8993(96)00056-X. PMID   8782860. S2CID   6178161.
  2. 1 2 Glick SD, Sell EM, Maisonneuve IM (December 2008). "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. doi:10.1016/j.ejphar.2008.09.038. PMC   2600595 . PMID   18930043.
  3. ↑ Taraschenko OD, Rubbinaccio HY, Maisonneuve IM, Glick SD (December 2008). "18-methoxycoronaridine: a potential new treatment for obesity in rats?". Psychopharmacology. 201 (3): 339–50. doi:10.1007/s00213-008-1290-9. PMC   3787601 . PMID   18751969.
  4. ↑ "Mindmed Acquires Opioid Addiction Drug Candidate Based on the Natural Psychedelic Ibogaine". www.newswire.ca. Retrieved 2025-11-25.
  5. ↑ "MindMed Reports Topline Data From Phase 1 Trial of MM-110 in Development for the Treatment of Opioid Withdrawal - MindMed". Archived from the original on 2022-07-03. Retrieved 2025-11-25.
  6. ↑ "MindMed Investor Presentation" (PDF). Archived (PDF) from the original on 2023-09-30.
  7. ↑ "FORM 10-K - Mind Medicine (MindMed) Inc" (PDF). Archived from the original (PDF) on 2025-03-15.
  8. ↑ "ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2025-11-25.
  9. ↑ Maisonneuve IM, Glick SD (June 2003). "Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment". Pharmacology, Biochemistry, and Behavior. 75 (3): 607–18. doi:10.1016/S0091-3057(03)00119-9. PMID   12895678. S2CID   26758480.
  10. ↑ Antonio T, Childers SR, Rothman RB, Dersch CM, King C, Kuehne M, et al. (2013). "Effect of Iboga alkaloids on μ-opioid receptor-coupled G protein activation". PLOS ONE. 8 (10) e77262. Bibcode:2013PLoSO...877262A. doi: 10.1371/journal.pone.0077262 . PMC   3818563 . PMID   24204784.
  11. ↑ 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.
  12. ↑ Glick SD, Ramirez RL, Livi JM, Maisonneuve IM (May 2006). "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. doi:10.1016/j.ejphar.2006.03.045. PMID   16626688.
  13. ↑ Taraschenko OD, Shulan JM, Maisonneuve IM, Glick SD (July 2007). "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. doi:10.1002/syn.20396. PMID   17447255. S2CID   2252348.
  14. ↑ Taraschenko OD, Rubbinaccio HY, Shulan JM, Glick SD, Maisonneuve IM (July 2007). "Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats". Neuropharmacology. 53 (1): 18–26. doi:10.1016/j.neuropharm.2007.04.010. PMC   2025684 . PMID   17544456.
  15. ↑ Arias HR, Tae HS, Micheli L, Yousuf A, Ghelardini C, Adams DJ, Di Cesare Mannelli L (September 2020). "Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and CaV2.2 channels". Neuropharmacology . 175 108194. doi:10.1016/j.neuropharm.2020.108194. hdl: 2158/1213504 . PMID   32540451. S2CID   219705597.
  16. ↑ Kuehne ME, He L, Jokiel PA, Pace CJ, Fleck MW, Maisonneuve IM, et al. (June 2003). "Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents". Journal of Medicinal Chemistry. 46 (13): 2716–30. doi:10.1021/jm020562o. PMID   12801235.
  17. ↑ Pace CJ, Glick SD, Maisonneuve IM, He LW, Jokiel PA, Kuehne ME, Fleck MW (May 2004). "Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration". European Journal of Pharmacology. 492 (2–3): 159–67. doi:10.1016/j.ejphar.2004.03.062. PMID   15178360.
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