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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Noribogaine |
| Topics | Ibogaine |
| Keywords | Antagonist Pharmacology Functional selectivity Partial agonist Intrinsic activity G protein-coupled receptor Arrestin Κ-opioid receptor Μ-opioid receptor Dynorphin a Opioid peptide Biochemistry |
| Citations | 1 |
| Key findings | 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.
Comparable studies
Other experimental studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. In vitro (SERT) | 2007 | Laboratory study | |
| Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. | 1992 | Laboratory study | |
| The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. | 2012 | Experimental study | |
| Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. | 1995 | Experimental study | |
| Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. | 1995 | Laboratory study |