Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.
Tamara Antonio, Steven R Childers, Richard B Rothman, Christina M Dersch, Christine King, Martin E. Kuehne, William G Bornmann, Amy J. Eshleman, Aaron Janowsky, Eric R Simon, Maarten E.A. Reith, Kenneth Alper
PLoS One 2013 DOI: 10.1371/journal.pone.0077262 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rat brain tissue and cultured cells overexpressing μ-opioid receptors |
| Interventions | Ibogaine noribogaine 18-methoxycoronaridine (18-MC) |
| Topics | Ibogaine |
| Keywords | Opioid withdrawal treatment Addiction recovery Substance abuse therapy Opioid dependence treatment Treatment development Ibogaine pharmacology Iboga alkaloids mechanism Drug action Receptor interaction Mechanism of action Opioid receptors Antagonists Novel therapeutic mechanisms Drug discovery New treatment pathways Innovative pharmacology |
| Citations | 36 |
| Key findings | Ibogaine, noribogaine, and 18-MC act as μ-opioid receptor antagonists, not agonists, in rat thalamic membranes and do not stimulate MOR-related G protein activity in most cell types, indicating a novel mechanism for their effects on opioid withdrawal. |
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.