title: Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.
abstract: OBJECTIVE
  The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.
  
  
  METHODS
  Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.
  
  
  CONCLUSIONS
  In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, New York, United States of America ; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.forename: Steven R
authors.initials: SR
authors.lastname: Childers
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Christine
authors.initials: C
authors.lastname: King
authors.forename: Martin
authors.initials: M
authors.lastname: Kuehne
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Eshleman
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
authors.forename: Eric R
authors.initials: ER
authors.lastname: Simon
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.forename: Kenneth
authors.initials: K
authors.lastname: Alper
mesh_terms: D000818:Animals; D001345:Autoradiography; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control; D013788:Thalamus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001952:Bridged-Ring Compounds; D017450:Receptors, Opioid, mu; C413805:ibogamine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007050:Ibogaine; C094385:noribogaine; C103345:18-methoxycoronaridine