{{Short description|Chemical compound}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 477209336 | INN = Zolunicant | IUPAC_name = 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 | image = 18-Methoxycoronaridine.svg | image_class = skin-invert-image | width = 225px | image2 = 18-methoxycoronaridine 3D BS.png | image_class2 = bg-transparent | width2 = 225px
<!--Clinical data--> | tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = IND | legal_US_comment = (filed 2/9/2014) | routes_of_administration = Oral
<!--Pharmacokinetic data--> | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =
<!--Identifiers--> | index2_label = racemic | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 308123-60-6 | CAS_number2_Ref = {{cascite|correct|CAS}} | CAS_number2 = 188125-42-0 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = KX8NQX91Z8 | UNII2_Ref = {{fdacite|correct|FDA}} | UNII2 = VG463BM9RL | ATC_prefix = | ATC_suffix = | PubChem = 10248465 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 24721799 | synonyms = 18-MC; Zolunicant; MM-110; MM110
<!--Chemical data--> | C=22 | H=28 | N=2 | O=3 | smiles = COCC[C@H]1C[C@@H]2C[C@@]3([C@H]1N(C2)CCc4c3[nH]c5c4cccc5)C(=O)OC | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = DTJQBBHYRQYDEG-SVBQBFEESA-N }} '''18-Methoxycoronaridine''' ('''18-MC; developmental code name MM-110'''), also known as '''zolunicant''' ({{Abbrlink|INN|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.
18-MC was originally developed by Savant HWP and later acquired by MindMed in 2019 for development as a treatment for opioid use disorder.<ref>{{Cite web | title=Mindmed Acquires Opioid Addiction Drug Candidate Based on the Natural Psychedelic Ibogaine | url=https://www.newswire.ca/news-releases/mindmed-acquires-opioid-addiction-drug-candidate-based-on-the-natural-psychedelic-ibogaine-891112447.html | access-date=2025-11-25 | website=www.newswire.ca}}</ref> A Phase 1 trial in healthy volunteers was completed in 2022 with favorable safety and tolerability.<ref>{{Cite web | title=MindMed Reports Topline Data From Phase 1 Trial of MM-110 in Development for the Treatment of Opioid Withdrawal - MindMed | url=https://mindmed.co/news/press-release/mindmed-reports-topline-data-from-phase-1-trial-of-mm-110-in-development-for-the-treatment-of-opioid-withdrawal/ | archive-url=https://web.archive.org/web/20220703234333/https://mindmed.co/news/press-release/mindmed-reports-topline-data-from-phase-1-trial-of-mm-110-in-development-for-the-treatment-of-opioid-withdrawal/ | access-date=2025-11-25 | archive-date=2022-07-03}}</ref> 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.<ref>{{Cite web| title=MindMed Investor Presentation | url-status=live | url=https://mindmed.co/wp-content/uploads/2023/06/MindMed-Investor-Day-2023-Presentation.pdf | archive-url=https://web.archive.org/web/20230930231631/https://mindmed.co/wp-content/uploads/2023/06/MindMed-Investor-Day-2023-Presentation.pdf | archive-date=2023-09-30}}</ref><ref>{{Cite web| title=FORM 10-K - Mind Medicine (MindMed) Inc. | url=https://ir.mindmed.co/sec-filings/all-sec-filings/content/0000950170-25-034176/0000950170-25-034176.pdf | archive-url=https://web.archive.org/web/20250315034141/https://ir.mindmed.co/sec-filings/all-sec-filings/content/0000950170-25-034176/0000950170-25-034176.pdf | archive-date=2025-03-15}}</ref> A separate Phase 2 trial in Brazil for cutaneous leishmaniasis (initiated 2017) has unknown status with no published results.<ref>{{Cite web | title=ClinicalTrials.gov | url=https://clinicaltrials.gov/study/NCT03084952 | access-date=2025-11-25 | website=clinicaltrials.gov}}</ref>
== Pharmacology == 18-MC is a α<sub>3</sub>β<sub>4</sub> nicotinic antagonist and, in contrast to ibogaine, has no affinity at the α<sub>4</sub>β<sub>2</sub> subtype nor at NMDA-channels nor at the serotonin transporter,<ref>{{cite journal | vauthors = Maisonneuve IM, Glick SD | title = Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment | journal = Pharmacology, Biochemistry, and Behavior | volume = 75 | issue = 3 | pages = 607–18 | date = June 2003 | pmid = 12895678 | doi = 10.1016/S0091-3057(03)00119-9 | s2cid = 26758480 }}</ref> 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,<ref name="pmid24204784">{{cite journal | vauthors = Antonio T, Childers SR, Rothman RB, Dersch CM, King C, Kuehne M, Bornmann WG, Eshleman AJ, Janowsky A, Simon ER, Reith ME, Alper K | display-authors = 6 | title = Effect of Iboga alkaloids on μ-opioid receptor-coupled G protein activation | journal = PLOS ONE | volume = 8 | issue = 10 |article-number=e77262 | year = 2013 | pmid = 24204784 | pmc = 3818563 | doi = 10.1371/journal.pone.0077262 | bibcode = 2013PLoSO...877262A | doi-access = free }}</ref> and κ-opioid receptors.<ref>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.</ref> The sites of action in the brain include the medial habenula, interpeduncular nucleus,<ref>{{cite journal | vauthors = Glick SD, Ramirez RL, Livi JM, Maisonneuve IM | title = 18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats | journal = European Journal of Pharmacology | volume = 537 | issue = 1–3 | pages = 94–8 | date = May 2006 | pmid = 16626688 | doi = 10.1016/j.ejphar.2006.03.045 }}</ref><ref>{{cite journal | vauthors = Taraschenko OD, Shulan JM, Maisonneuve IM, Glick SD | title = 18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens | journal = Synapse | volume = 61 | issue = 7 | pages = 547–60 | date = July 2007 | pmid = 17447255 | doi = 10.1002/syn.20396 | s2cid = 2252348 }}</ref><ref>{{cite journal | vauthors = Taraschenko OD, Rubbinaccio HY, Shulan JM, Glick SD, Maisonneuve IM | title = Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats | journal = Neuropharmacology | volume = 53 | issue = 1 | pages = 18–26 | date = July 2007 | pmid = 17544456 | pmc = 2025684 | doi = 10.1016/j.neuropharm.2007.04.010 }}</ref> dorsolateral tegmentum and basolateral amygdala.<ref name="Brain regions mediating alpha3beta4">{{cite journal | vauthors = Glick SD, Sell EM, Maisonneuve IM | title = Brain regions mediating alpha3beta4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration | journal = European Journal of Pharmacology | volume = 599 | issue = 1–3 | pages = 91–5 | date = December 2008 | pmid = 18930043 | pmc = 2600595 | doi = 10.1016/j.ejphar.2008.09.038 }}</ref> (±)-18-MC competitively inhibits α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly blocks Ca<sub>V</sub>2.2.<ref name="pmid32540451">{{cite journal |vauthors=Arias HR, Tae HS, Micheli L, Yousuf A, Ghelardini C, Adams DJ, Di Cesare Mannelli L |title=Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and CaV2.2 channels |journal=Neuropharmacology |volume=175 |issue= |article-number=108194 |date=September 2020 |pmid=32540451 |doi=10.1016/j.neuropharm.2020.108194 |url= https://ro.uow.edu.au/ihmri/1536|issn=|hdl=2158/1213504 |s2cid=219705597 |hdl-access=free }}</ref>
==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 α<sub>3</sub>β<sub>4</sub> nicotinic acetylcholine antagonists, with little or no effect on NMDA receptors.<ref>{{cite journal | vauthors = Kuehne ME, He L, Jokiel PA, Pace CJ, Fleck MW, Maisonneuve IM, Glick SD, Bidlack JM | display-authors = 6 | title = Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 13 | pages = 2716–30 | date = June 2003 | pmid = 12801235 | doi = 10.1021/jm020562o }}</ref><ref>{{cite journal | vauthors = Pace CJ, Glick SD, Maisonneuve IM, He LW, Jokiel PA, Kuehne ME, Fleck MW | title = Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration | journal = European Journal of Pharmacology | volume = 492 | issue = 2–3 | pages = 159–67 | date = May 2004 | pmid = 15178360 | doi = 10.1016/j.ejphar.2004.03.062 }}</ref> class=skin-invert-image|500px
== See also == * Coronaridine * Ibogaine * Noribogaine * Voacangine
== References == {{Reflist|2}}
{{Ionotropic glutamate receptor modulators}} {{Nicotinic acetylcholine receptor modulators}} {{Opioid receptor modulators}} {{Sigma receptor modulators}}
{{DEFAULTSORT:Methoxycoronaridine, 18-}} Category:Drug rehabilitation Category:Tabernanthe iboga Category:Nicotinic antagonists Category:Kappa-opioid receptor agonists Category:Mu-opioid receptor antagonists Category:Opioid modulators