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.