Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors.
Neurochemistry international – September 01, 2010
Source: PubMed
Summary
Certain plant-derived molecules, including ibogaine, are found to effectively block muscle nerve receptors. These compounds achieve this by noncompetitively inhibiting calcium influx and binding with high affinity to the receptors when they are in a desensitized state, essentially turning off nerve signals. Docking experiments reveal that these plant molecules share an overlapping binding site within the receptor's ion channel with phencyclidine (PCP), forming similar chemical bonds. This discovery highlights a crucial structural requirement for inhibiting these receptors, providing valuable insights into their powerful effects and potential for therapeutic development.
Abstract
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 Ca(2+) influx in TE671-halpha1beta1gammadelta cells with similar potencies (IC(50)=17-25microM), (b) inhibit [(3)H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR, and (c) enhance [(3)H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties. Interestingly, PCP inhibits [(3)H]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 AChR inhibition including, ion channel blocking and desensitization, and that ibogaine and PCP bind to overlapping sites in the desensitized AChR ion channel.