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18-Methoxycoronaridine

Chemical compound

18-Methoxycoronaridine

Chemical compound

FieldValue
Verifiedfieldschanged
Watchedfieldschanged
verifiedrevid477209336
INNZolunicant
IUPAC_namemethyl (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
image18-Methoxycoronaridine.svg
image_classskin-invert-image
width225px
image218-methoxycoronaridine 3D BS.png
image_class2bg-transparent
width2225px
legal_USIND
legal_US_comment(filed 2/9/2014)
routes_of_administrationOral
index2_labelracemic
CAS_number_Ref
CAS_number308123-60-6
CAS_number2_Ref
CAS_number2188125-42-0
UNII_Ref
UNIIKX8NQX91Z8
UNII2_Ref
UNII2VG463BM9RL
PubChem10248465
ChemSpiderID_Ref
ChemSpiderID24721799
synonyms18-MC; Zolunicant; MM-110; MM110
C22H=28N=2O=3
smilesCOCC[C@H]1C[C@@H]2C[C@@]3([C@H]1N(C2)CCc4c3[nH]c5c4cccc5)C(=O)OC
StdInChI_Ref
StdInChI1S/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
StdInChIKey_Ref
StdInChIKeyDTJQBBHYRQYDEG-SVBQBFEESA-N

| elimination_half-life =

18-Methoxycoronaridine (18-MC; developmental code name 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 proven to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine, and sucrose. 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.

18-MC was originally developed by Savant HWP and later acquired by MindMed in 2019 for development as a treatment for opioid use disorder. A Phase 1 trial in healthy volunteers was completed in 2022 with favorable safety and tolerability. 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. A separate Phase 2 trial in Brazil for cutaneous leishmaniasis (initiated 2017) has unknown status with no published results.

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, 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, and κ-opioid receptors. The sites of action in the brain include the medial habenula, interpeduncular nucleus, dorsolateral tegmentum and basolateral amygdala. (±)-18-MC competitively inhibits α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly blocks CaV2.2.

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.

References

References

  1. (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.
  2. (December 2008). "Brain regions mediating alpha3beta4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration". European Journal of Pharmacology.
  3. (December 2008). "18-methoxycoronaridine: a potential new treatment for obesity in rats?". Psychopharmacology.
  4. "Mindmed Acquires Opioid Addiction Drug Candidate Based on the Natural Psychedelic Ibogaine".
  5. "MindMed Reports Topline Data From Phase 1 Trial of MM-110 in Development for the Treatment of Opioid Withdrawal - MindMed".
  6. "MindMed Investor Presentation".
  7. "FORM 10-K - Mind Medicine (MindMed) Inc.".
  8. "ClinicalTrials.gov".
  9. (June 2003). "Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment". Pharmacology, Biochemistry, and Behavior.
  10. (2013). "Effect of Iboga alkaloids on μ-opioid receptor-coupled G protein activation". PLOS ONE.
  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. (May 2006). "18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats". European Journal of Pharmacology.
  13. (July 2007). "18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens". Synapse.
  14. (July 2007). "Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats". Neuropharmacology.
  15. (September 2020). "Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and CaV2.2 channels". [[Neuropharmacology]].
  16. (June 2003). "Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents". Journal of Medicinal Chemistry.
  17. (May 2004). "Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration". European Journal of Pharmacology.
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drug-rehabilitation tabernanthe-iboga nicotinic-antagonists nmda-receptor-antagonists kappa-opioid-receptor-agonists mu-opioid-receptor-antagonists opioid-modulators
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