Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors.
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.
Arias
Hugo R
HR
Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, 19555 N. 59th Ave., Glendale, AZ 85308, USA. harias@midwestern.edu
Feuerbach
Dominik
D
Targowska-Duda
Katarzyna M
KM
Jozwiak
Krzysztof
K
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007050:Ibogaine / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D017136:Ion Transport; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014101:Torpedo; D014316:Tritium; D014748:Vinca Alkaloids / Q000494:pharmacology*
D007473:Ion Channels; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014748:Vinca Alkaloids; D014316:Tritium; D007050:Ibogaine; D002118:Calcium; C017836:catharanthine