Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states.
The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC (a) is more potent than ibogaine and PCP inhibiting (-)-epibatidine-induced AChR Ca(2) influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of (3)Hcytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits (3)HTCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6) and valine (position 13) rings, and (c) inhibits (3)HTCP, (3)Hibogaine, and (3)H18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.