Noribogaine is a G-protein biased κ-opioid receptor agonist.
Émeline L. Maillet, Nicolas Milon, Mari D. Heghinian, James A. Fishback, Stephan C. Schürer, Nandor Garamszegi, Deborah C. Mash
Neuropharmacology December 1, 2015 DOI: 10.1016/j.neuropharm.2015.08.032 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with binding experiments, functional assays, and computational simulations Peer reviewed |
|---|---|
| Intervention | Noribogaine |
| Dose | 40 mg/kg ibogaine in animals |
| Topics | Addiction Ibogaine |
| Keywords | 18-mc Analgesia Beta-arrestin pathway Biased agonist Computational simulation Functional selectivity G-protein pathway Kappa opioid receptor Mu opioid receptor Narcotic Noribogaine hydrochloride Opioid receptor pharmacology Dynorphin a Damgo Naloxone Nor-binaltorphimine U69 593 Nalmefene Addiction treatment Anti-addiction Pain management Morphine |
| Citations | 59 |
| Post-publication review | 2 comments on PubPeer (opens in new tab) · last active September 2021 |
| Key findings | Noribogaine is a G-protein biased kappa opioid receptor agonist and weak mu antagonist, with functional inhibition of dynorphin-induced β-arrestin recruitment, a unique pharmacology that may contribute to its anti-addictive and potential analgesic effects. |
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 (Ke) 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.
Comparable studies
Other experimental studies on ibogaine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Anti-addiction drug ibogaine inhibits hERG channels: a cardiac arrhythmia risk. Human cells | 2014 | Experimental study | |
| Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: a study to assess the drug's cardiac ion channel profile. Heterologously expressed human ion channels and guinea pig cardiomyocytes | 2013 | Experimental study | |
| Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound. C6 glioma cells | 2016 | Laboratory study | |
| Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation. Rat brain models | 2002 | Review with experimental data | |
| Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Human ventricular-like cardiomyocytes derived from induced pluripotent stem cells | 2017 | Experimental study |
Citations in the library
Cited by 16
- Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits. Frontiers in Pharmacology 2019
- A systematic literature review of clinical trials and therapeutic applications of ibogaine. Journal of Substance Abuse Treatment July 1, 2022
- DARK Classics in Chemical Neuroscience: Ibogaine ACS Chemical Neuroscience September 14, 2018
- Ibogaine as a treatment for substance misuse: Potential benefits and practical dangers. Progress in Brain Research 2018
- Psychedelic therapies reconsidered: compounds, clinical indications, and cautious optimism. Neuropsychopharmacology July 21, 2023
and 11 more in the library
Cites 23
- Treatment of acute opioid withdrawal with ibogaine. The American Journal on Addictions 1999
- A preliminary investigation of ibogaine: case reports and recommendations for further study. Journal of Substance Abuse Treatment 1994
- Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures. Annals of the New York Academy of Sciences September 1, 2000
- 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats. Brain Research May 6, 1996
- Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependencea. Annals of the New York Academy of Sciences May 1, 1998
and 18 more in the library