Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states.
The international journal of biochemistry & cell biology – September 01, 2011
Source: PubMed
Summary
Remarkably, subtle changes to ibogaine's structure can significantly boost its interaction with crucial brain receptors. Researchers investigated how ibogaine-like compounds bind to and affect nicotinic acetylcholine receptors, which play roles in addiction and cognition. Using functional tests and binding studies, they found that specific ibogaine analogs, like 18-methoxycoronaridine, are *more potent* than ibogaine itself at inhibiting receptor activity. These compounds preferentially bind to the receptor's 'desensitized' state, suggesting a mechanism for their action. A key discovery was an *optimal molecular size* for these compounds to effectively bind, indicating that the precise fit within a receptor pocket is critical for their strong effects.
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.