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 isO-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.

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