Noribogaine is a Mixed Agonist/Antagonist Opioid Ligand with Profound Functional Selectivity
Émeline L. Maillet, Nicolas Milon, James A. Fishback, Stephan C. Schürer, Mari D. Heghinian, Nandor Garamszegi, Deborah C. Mash
The FASEB Journal April 1, 2015 DOI: 10.1096/fasebj.29.1_supplement.lb505 via OpenAlex
Summary
AI-generated from the abstractNoribogaine, the primary metabolite of the anti-addictive substance ibogaine, modulates opioid receptors in ways that may explain its therapeutic effects. At mu-opioid receptors, noribogaine acts as a moderately potent antagonist of both G-protein and β-arrestin signaling pathways. At kappa-opioid receptors, it is a partial agonist of the G-protein pathway, activating at 75% the maximal efficacy of Dynorphin A with a potency of 9 µM, while poorly activating the β-arrestin pathway. Noribogaine functionally inhibits Dynorphin A-induced β-arrestin recruitment at physiologically relevant concentrations, with an IC50 of 1.45 µM. Computational simulations suggest noribogaine binds to the orthosteric morphinan binding site.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Noribogaine |
| Keywords | Antagonist Pharmacology Functional selectivity Partial agonist Intrinsic activity |
| Citations | 1 |
| Key finding | Noribogaine is a moderately potent antagonist at mu-opioid receptors and a biased partial agonist at kappa-opioid receptors, preferentially activating G-protein signaling over β-arrestin recruitment. |
Abstract
Noribogaine is the primary metabolite of the anti‐addictive substance ibogaine, which modulates opiate analgesic activity and the components of drug addiction in animal models at brain concentrations of 0.5‐15 µM. In this study, molecular activities of noribogaine at mu (OPRM) and kappa (OPRK) opioid receptors were characterized. Noribogaine was a moderately potent antagonist of the OPRM G‐protein and β‐arrestin signaling pathways (20 µM; 48 µM). Noribogaine was a partial agonist at the OPRK G‐protein pathway, activating at 75% the maximal efficacy of Dynorphin A (Dyn‐A) at a potency of 9 µM, and had weak inhibitory properties (40 µM, 25% against Dyn‐A). Noribogaine was a biased agonist and poorly activated the OPRK β‐arrestin pathway at 12% of Dyn‐A maximal efficacy. In turn, noribogaine was able to functionally inhibit Dyn‐A‐induced β‐arrestin recruitment (Dyn‐A EC 50 : 82 nM) at physiologically relevant concentrations (IC 50 of 1.45 µM at 370 nM Dyn‐A). Computational simulations indicated that noribogaine may bind to the orthosteric morphinan binding site of the receptor. This study clarifies the action of noribogaine at modulating opioid receptor function, uncovering explanatory mechanisms as well as new avenues of therapeutic development.