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

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...