Interaction of ibogaine with human alpha3beta4-nicotinic acetylcholine receptors in different conformational states.
Hugo R Arias, Avraham Rosenberg, Katarzyna M Targowska-Duda, Dominik Feuerbach, Xiao Juan Yuan, Krzysztof Jozwiak, Ruin Moaddel, Irving W. Wainer
The international journal of biochemistry & cell biology September 1, 2010 DOI: 10.1016/j.biocel.2010.05.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Human alpha3beta4-nicotinic acetylcholine receptors |
| Interventions | Ibogaine Phencyclidine |
| Topics | Ibogaine |
| Keywords | Ibogaine: ibogaine Human brain receptor Key brain receptors Receptor's channel Desensitized state Inactive phase Shut down state Blocks Inhibiting Potency Binds strongly Potential therapeutic actions Pcp comparison: pcp |
| Citations | 29 |
| Key findings | Ibogaine binds with higher potency than PCP to a single site in the human alpha3beta4 AChR ion channel and dissociates more slowly from the desensitized state, likely prolonging receptor desensitization. |
Abstract
The interaction of ibogaine and phencyclidine (PCP) with human (h) alpha3beta4-nicotinic acetylcholine receptors (AChRs) in different conformational states was determined by functional and structural approaches including, radioligand binding assays, Ca2+ influx detections, and thermodynamic and kinetics measurements. The results established that (a) ibogaine inhibits (+/-)-epibatidine-induced Ca2+ influx in h(alpha)3beta4 AChRs with approximately 9-fold higher potency than that for PCP, (b) [3H]ibogaine binds to a single site in the h(alpha)3beta4 AChR ion channel with relatively high affinity (Kd = 0.46 +/- 0.06 microM), and ibogaine inhibits [3H]ibogaine binding to the desensitized h(alpha)3beta4 AChR with slightly higher affinity compared to the resting AChR. This is explained by a slower dissociation rate from the desensitized ion channel compared to the resting ion channel, and (c) PCP inhibits [3H]ibogaine binding to the h(alpha)3beta4 AChR, suggesting overlapping sites. The experimental results correlate with the docking simulations suggesting that ibogaine and PCP interact with a binding domain located between the serine (position 6') and valine/phenylalanine (position 13') rings. This interaction is mediated mainly by van der Waals contacts, which is in agreement with the observed enthalpic contribution determined by non-linear chromatography. However, the calculated entropic contribution also indicates local conformational changes. Collectively our data suggest that ibogaine and PCP bind to overlapping sites located between the serine and valine/phenylalanine rings, to finally block the AChR ion channel, and in the case of ibogaine, to probably maintain the AChR in the desensitized state for longer time.
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 |
Citations in the library
Cited by 14
- Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits. Frontiers in Pharmacology 2019
- Psychedelics as a novel approach to treating autoimmune conditions Immunology Letters October 6, 2020
- 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
- IUPHAR - invited review - Ibogaine - A legacy within the current renaissance of psychedelic therapy. Pharmacological Research April 1, 2023
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Cites 10
- Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine Journal of Pharmacology and Experimental Therapeutics 1999
- Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. European Journal of Pharmacology March 1, 2002
- Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacology, Biochemistry, and Behavior June 1, 2003
- 18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action. Annals of the New York Academy of Sciences September 1, 2000
- Ibogaine: a potent noncompetitive blocker of ganglionic/neuronal nicotinic receptors. Molecular Pharmacology 1997
and 5 more in the library