Noribogaine is a Mixed Agonist/Antagonist Opioid Ligand with Profound Functional Selectivity

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 EC50: 82 nM) at physiologically relevant concentrations (IC50 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.