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Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states

2010; Elsevier BV; Volume: 1798; Issue: 6 Linguagem: Inglês

10.1016/j.bbamem.2010.03.013

1879-2642

Hugo R. Arias, Avraham Rosenberg, Dominik Feuerbach, Katarzyna M. Targowska‐Duda, Ryszard Maciejewski, Krzysztof Jóźwiak, Ruin Moaddel, Stanley D. Glick, Irving W. Wainer,

Ion channel regulation and function

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 Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP 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 [3H]TCP, [3H]ibogaine, and [3H]18-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.