Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

Iboga alkaloids, including ibogaine, its metabolite noribogaine, and the synthetic compound 18-methoxycoronaridine (18-MC), were tested for their ability to activate the μ-opioid receptor (MOR), a common target of opioid drugs. In rat thalamic membranes, all three compounds acted as antagonists, blocking the receptor rather than activating it, with functional Ke values ranging from 3 μM for ibogaine to 13 μM for noribogaine and 18-MC. None of the compounds stimulated MOR-related G protein activity in cells expressing human or rat MORs, and only limited partial agonist effects were seen in mouse MOR-expressing cells. The findings indicate that an opioid agonist mechanism does not explain these alkaloids' effects on opioid withdrawal, supporting a novel mechanism of action and justifying further search for alternative targets.

Study at a glance

Abstract

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. 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. 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.