Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states.

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.

Study at a glance

Abstract

The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca²⁺ influx in human embryonic muscle AChRs with the following potency sequence (IC(50) in μM): (±)-18-methylaminocoronaridine (5.9±0.3)∼(±)-18-methoxycoronaridine (18-MC) (6.8±0.8)>(-)-ibogaine (17±3)∼(+)-catharanthine (20±1)>(±)-albifloranine (46±13), (b) bind to the [³H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [³H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [³H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC₅₀) that correlate very well with the pK(i) values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ∼345 ų for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization.