Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and 18-Methoxycoronaridine: Difference between pages

{{Short description|Chemical compound}}

| Watchedfields = changed

| verifiedrevid = 477209336

| synonyms = {{bulleted list| (−)-18-methoxycoronaridine| 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

| image2 = 18-methoxycoronaridine 3D BS.png

| width2 = 180

| tradename =

| legal_US = IND

| legal_US_comment = (filed 2/9/2014)

| routes_of_administration = [[Oral administration|Oral]]

| excretion =

| 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

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 24721799

| 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, 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]].<ref>{{cite journal | vauthors = Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH | title = 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats | journal = Brain Research | volume = 719 | issue = 1–2 | pages = 29–35 | date = May 1996 | pmid = 8782860 | doi = 10.1016/0006-8993(96)00056-X | s2cid = 6178161 }}</ref><ref>{{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> 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.<ref>{{cite journal | vauthors = Taraschenko OD, Rubbinaccio HY, Maisonneuve IM, Glick SD | title = 18-methoxycoronaridine: a potential new treatment for obesity in rats? | journal = Psychopharmacology | volume = 201 | issue = 3 | pages = 339–50 | date = December 2008 | pmid = 18751969 | pmc = 3787601 | doi = 10.1007/s00213-008-1290-9 }}</ref>

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.<ref name="newswire.ca">[https://www.newswire.ca/news-releases/mindmed-acquires-opioid-addiction-drug-candidate-based-on-the-natural-psychedelic-ibogaine-891112447.html Mindmed Acquires Opioid Addiction Drug Candidate Based on the Natural Psychedelic Ibogaine] newswire.ca September 16, 2019.</ref><ref name="timesunion.com">[http://www.timesunion.com/local/article/Albany-Med-scientist-closer-to-addiction-drug-5585843.php Albany Med scientist closer to addiction drug success] timesunion.com June 27, 2014.</ref> In 2002 the research team began raising funds for human trials, but were unable to secure the estimated $5 million needed.<ref>Addiction Treatment Strives for Legitimacy. ''Journal of the American Medical Association''. 2002; 288: 3096-3101.</ref> 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 [[wikt:congener|congener]]s. In 2012 the [[National Institute on Drug Abuse]] gave a $6.5 million grant to Savant HWP for human trials.<ref name="timesunion.com"/> In 2017 it went into Phase-II trials in Brazil for treatment of [[Leishmaniasis]] at the [[Evandro Chagas Institute]],<ref>{{cite web |title=Phase 2 Trial to Evaluate 18-Methoxycoronaridine Efficacy, Safety and Tolerability in Cutaneous Leishmaniasis Patients |url=https://clinicaltrials.gov/ct2/show/NCT03084952 |website=ClinicalTrials.gov |access-date=19 February 2020}}</ref> 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.<ref>{{cite web |title= Opioid Use Disorder: Zolunicant's Potential for Unmet Treatment Needs |date= 20 May 2022 |url= https://mindmed.co/news/video/opioid-use-disorder-zolunicants-potential-for-unmet-treatment-needs/ |publisher=MindMed.co |access-date=23 May 2022}}</ref>

== Pharmacology ==

18-MC is a [[ganglion type nicotinic receptor|α₃β₄]] [[nicotinic acetylcholine receptor|nicotinic antagonist]] and, in contrast to ibogaine, has no affinity at the [[Alpha-4 beta-2 nicotinic receptor|α₄β₂]] subtype nor at [[NMDA|NMDA-channel]]s 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 channel]]s and for the [[sigma receptor|σ receptor]], but retains modest affinity for [[mu opioid receptor|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 | pages = e77262 | year = 2013 | pmid = 24204784 | pmc = 3818563 | doi = 10.1371/journal.pone.0077262 | bibcode = 2013PLoSO...877262A | doi-access = free }}</ref> and [[kappa opioid receptor|κ-opioid receptor]]s.<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>{{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 [[nicotinic acetylcholine receptor|nAChRs]] with potencies higher than that at α3β4 and α4β2 nAChRs and directly blocks [[N-type calcium channel|Ca_V2.2]].<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= |pages=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 [[2-Methoxyethyl-18-methoxycoronaridinate|ME-18-MC]] being more potent than 18-MC with similar efficacy, and the methylamino analogue [[18-Methylaminocoronaridine|18-MAC]] being more effective than 18-MC with around the same potency. These compounds were also found to act as selective [[ganglion type nicotinic receptor|α₃β₄ 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>

[[File:iboga alkaloids.png|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:Iboga]]

[[Category:Nicotinic antagonists]]

[[Category:NMDA receptor antagonists]]

[[Category:Kappa-opioid receptor agonists]]

[[Category:Mu-opioid receptor antagonists]]

[[Category:Opioid modulators]]