Neuropharmacology
December 1, 2015
Emeline L Maillet, Nicolas Milon, Mari D Heghinian et al.
59 citations
Noribogaine, the main human metabolite of the anti-addictive substance ibogaine, reaches brain concentrations up to 20 μM after a therapeutic dose. Binding experiments and computational simulations indicate it may bind to the orthosteric morphinan site of opioid receptors. Noribogaine is a weak mu opioid receptor antagonist (Ke=20 μM at both G-protein and β-arrestin pathways) but a G-protein biased kappa opioid receptor agonist: 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50=9 μM) yet only 12% as efficacious at recruiting β-arrestin. It also functionally inhibits dynorphin-induced kappa β-arrestin recruitment (IC50=1 μM), more potent than its G-protein agonism.
The FASEB Journal
April 1, 2015
Émeline L. Maillet, Nicolas Milon, James A. Fishback et al.
1 citation
Noribogaine, 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.
The FASEB Journal
April 1, 2015
Émeline L. Maillet, Qing Chang, Nicolas Milon et al.
Noribogaine, a drug that acts on opioid receptors, nicotinic receptors, and serotonin transporters, was tested for its effects on nicotine dependence. It inhibited several types of nicotinic acetylcholine receptors, including α3β4 and α7. In a rat model of nicotine self-administration, noribogaine dose-dependently reduced nicotine intake by up to 64% compared to saline-treated rats, an effect comparable to the approved smoking cessation drug varenicline. These results suggest noribogaine may have potential for treating smoking cessation, substance abuse, and anxiety disorders.