Interaction of ibogaine with human alpha3beta4-nicotinic acetylcholine receptors in different conformational states.
The international journal of biochemistry & cell biology – September 01, 2010
Source: PubMed
Summary
A fascinating finding reveals that ibogaine not only blocks key brain receptors but also keeps them in a 'quiet' state for longer. Researchers investigated how ibogaine and PCP interact with a specific type of human brain receptor using various lab tests and simulations. They found ibogaine is nine times more potent than PCP at inhibiting these receptors. Ibogaine binds strongly to a specific site within the receptor's channel, and uniquely, it binds even more tightly to receptors already in a desensitized state, prolonging this inactive phase. This suggests ibogaine effectively blocks receptor activity by stabilizing a 'shut down' state, offering insights into its potential therapeutic actions.
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.