Abstract
ObjectiveThe 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.MethodsIbogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.Results And SignificanceIn 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 [35S]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 [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]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.
Highlights
The iboga alkaloids are a class of approximately 80 known naturally occurring and synthetic monoterpene indole alkaloids defined structurally on the basis of a common ibogamine skeleton [1,2] (Fig. 1)
We found that noribogaine and 18-MC have only limited, partial agonist effects in some MC bind to the μopioid receptor (MOR) expressing cells and do not stimulate [35S]GTPγS binding at all in others, and ibogaine did not did not stimulate [35S]GTPγS binding in any MOR expressing cells
Noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM to 13 uM in rat thalamic membranes
Summary
The iboga alkaloids are a class of approximately 80 known naturally occurring and synthetic monoterpene indole alkaloids defined structurally on the basis of a common ibogamine skeleton [1,2] (Fig. 1). As novel small molecules that modify opioid withdrawal and drug self-administration, iboga alkaloids are of interest with regard to their potential for neurobiological investigation and drug development. Occurs in the root bark of the West African shrub Tabernanthe iboga Baill. In West Central Africa eboga, crude T. iboga root bark, has been used as a sacramental hallucinogen in the Bwiti religion for centuries [3]. The National Institute on Drug Abuse (NIDA) has recently committed 3.6 million USD support to date for preclinical testing and chemical manufacturing and control work intended to enable clinical trials to develop the synthetic iboga alkaloid 18-methoxycoronaridine (18-MC) as a pharmacotherapy for addiction [7]
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