The international journal of biochemistry & cell biology
September 1, 2010
Hugo R Arias, Avraham Rosenberg, Katarzyna M Targowska-Duda et al.
29 citations
Ibogaine blocks human alpha3beta4-nicotinic acetylcholine receptors (AChRs) by binding to a site in the receptor's ion channel, with about nine times higher potency than phencyclidine (PCP). Ibogaine binds with relatively high affinity (Kd = 0.46 ± 0.06 μM) to a single site in the channel and dissociates more slowly from the desensitized receptor than from the resting one, which may prolong the desensitized state. PCP inhibits ibogaine binding, indicating overlapping binding sites between the serine and valine/phenylalanine rings. The interaction is mainly via van der Waals contacts, with local conformational changes suggested by entropic contributions. These findings suggest ibogaine's mechanism involves stabilizing the receptor in a shut-down state.
The international journal of biochemistry & cell biology
September 1, 2011
Hugo R Arias, Dominik Feuerbach, Katarzyna M Targowska-Duda et al.
10 citations
Ibogaine analogs inhibit epibatidine-induced calcium influx in human muscle acetylcholine receptors with a potency order: 18-methylaminocoronaridine and 18-methoxycoronaridine are most potent, followed by ibogaine and catharanthine, then albifloranine. The analogs bind more strongly to the TCP binding site when the receptor is in the desensitized state versus the resting state, and they enhance cytisine binding to resting receptors. The affinity of the analogs correlates with their molecular volume, with an optimal volume around 345 cubic angstroms for the ibogaine site, suggesting the size of the binding site between the serine and nonpolar rings is crucial for binding and desensitization.
Neurochemistry international
September 1, 2010
Hugo R Arias, Dominik Feuerbach, Katarzyna M Targowska-Duda et al.
9 citations
Catharanthine alkaloids such as ibogaine, vincristine, and vinblastine inhibit muscle nicotinic acetylcholine receptors (AChRs) in a noncompetitive manner, blocking ion flow and promoting receptor desensitization. These compounds inhibit epibatidine-induced calcium influx in TE671 cells with similar potencies (IC50 = 17–25 μM). They bind more tightly to desensitized than resting AChRs and enhance binding of cytisine to resting receptors, indicating desensitizing properties. Phencyclidine (PCP) inhibits ibogaine binding to the AChR through steric hindrance. Docking experiments suggest neutral ibogaine forms hydrogen bonds with the serine ring at position 6', a site shared with PCP, while protonated ibogaine may form a salt bridge with acidic residues at the outer ring. The catharanthine moiety is the minimal structure required for AChR inhibition.