Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine

• Published in: Psychopharmacology Vol. 127; no. 1; p. 10
• Main Authors: Staley, J K, Ouyang, Q, Pablo, J, Hearn, W L, Flynn, D D, Rothman, R B, Rice, K C, Mash, D C
• Format: Journal Article
• Language: English
• Published: Germany 01.09.1996
• Subjects: Binding Sites; Brain - metabolism; Brain Stem - chemistry; Cerebellum - chemistry; Cerebral Cortex - chemistry; Corpus Striatum - chemistry; Dopamine - metabolism; Gas Chromatography-Mass Spectrometry; Humans; Ibogaine - analogs & derivatives; Ibogaine - analysis; Ibogaine - metabolism; Ibogaine - pharmacology; Radioligand Assay; Receptors, N-Methyl-D-Aspartate - metabolism; Serotonin - metabolism
• ISSN: 0033-3158
• DOI: 10.1007/BF02805969

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.