title: Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine.
abstract: The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and is O-demethylated to 12-hydroxyibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [3H]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine's ability to alter drug-seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits.
authors.affiliation: Department of Neurology (D4-5), University of Miami School of Medicine, FL 33101, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Staley
authors.forename: Q
authors.initials: Q
authors.lastname: Ouyang
authors.forename: J
authors.initials: J
authors.lastname: Pablo
authors.forename: W L
authors.initials: WL
authors.lastname: Hearn
authors.forename: D D
authors.initials: DD
authors.lastname: Flynn
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: D C
authors.initials: DC
authors.lastname: Mash
mesh_terms: D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D001933:Brain Stem / Q000737:chemistry; D002531:Cerebellum / Q000737:chemistry; D002540:Cerebral Cortex / Q000737:chemistry; D003342:Corpus Striatum / Q000737:chemistry; D004298:Dopamine / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D007050:Ibogaine; C094385:noribogaine; D004298:Dopamine