Noribogaine is a G-Protein Biased κ-Opioid Receptor Agonist

This study examines the specific roles and activities of noribogaine at the opioid receptors in relation to physiological outputs in order to characterize noribogaine to the mu (OPRM) and the kappa (OPRK) opioid receptors. The study observed that the biased agonist/antagonist pharmacology is distinctive to noribogaine in comparison to other ligands including ibogaine, nalmefene, 18-MC, and 6′-GNTI. It predicted that noribogaine promoted some analgesic effects and anti-addictive response.

Abstract

“Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (K_e) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC₅₀ = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC₅₀ of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6′-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.“

Authors: Emeline L. Maillet, Nicolas Milon, Mari D. Heghinian, James Fishback, Stephan C. Schürer, Nandor Garamszegi & Deborah C. Mash