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Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors

Arias, HR, Feuerbach, Dominik, Targowska-Duda, KM and Jozwiak, Krysztof (2010) Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors. Neurochemistry international.


We compared the interaction of several catharanthine alkaloids including, ibogaine, vincristine, and vinblastine, with that for the noncompetitive antagonist phencyclidine (PCP) at muscle nicotinic acetylcholine receptors (AChRs) in different conformational states. The results established that catharanthine alkaloids: (a) inhibit, in a noncompetitive manner, (±)-epibatidine-induced Ca2+ influx in TE671-hα1β1γδ AChR cells with similar potencies (17-25 μM), (b) inhibit [3H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR, and (c) enhance [3H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties. Interestingly, PCP inhibits [3H]ibogaine binding to the AChR in a steric fashion. This is corroborated by additional docking experiments indicating that the amino groups of neutral ibogaine form hydrogen bonds with the serine ring (position 6’), a location shared with PCP. Since protonated ibogaine forms a salt bridge with one of the acidic residues at the outer ring (position 20’), this ligand could be first attracted to the entrance of the channel by electrostatic interactions. Our data indicate that the catharanthine moiety is a minimum structural requirement for ion channel inhibition, and that ibogaine and PCP bind to overlapping sites in the desensitized AChR ion channel. In addition, catharanthine alkaloids may inhibit ion channel function by inducing AChR desensitization

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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