Cholinergic drugs potentiate human nicotinic alpha4beta2 acetylcholine receptors by a competitive mechanism.
Effects of cholinergic drugs on human alpha4beta2 nicotinic acetylcholine receptors expressed in Xenopus oocytes have been investigated in electrophysiological and ligand binding experiments. Atropine, scopolamine, physostigmine, and tacrine combine potentiation of ion current induced by low concentrations of acetylcholine with inhibition of ion current evoked by high concentrations of acetylcholine. Rivastigmine, galanthamine, and dichlorvos cause only inhibition of ion current evoked by low concentrations of acetylcholine. Binding experiments show that the potentiating cholinergic drugs atropine, scopolamine, and physostigmine are competitive ligands of human alpha4beta2 nicotinic acetylcholine receptors. Conversely, the inhibitory cholinergic drugs galanthamine and rivastigmine are non-competitive. The non-competitive drugs are not allosteric, since they do not affect the saturation curve of the radioligand [3H]cytisine. Effects of potentiating cholinergic drugs on nicotinic acetylcholine receptors are consistent with and predicted by a model comprising competitive drug effects at two equivalent agonist recognition sites on the nicotinic acetylcholine receptor combined with non-competitive ion channel block.
Smulders
Chantal J G M
CJ
Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80176, NL-3508 TD Utrecht, The Netherlands.
Zwart
Ruud
R
Bermudez
Isabel
I
van Kleef
Regina G D M
RG
Groot-Kormelink
Paul J
PJ
Vijverberg
Henk P M
HP
D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001392:Azocines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004006:Dichlorvos / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005702:Galantamine / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009538:Nicotine / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D048448:Phenylcarbamates / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011807:Quinolizines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000068836:Rivastigmine; D012601:Scopolamine / Q000494:pharmacology; D013619:Tacrine / Q000494:pharmacology; D014982:Xenopus laevis; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D001285:Atropine; D001392:Azocines; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D004006:Dichlorvos; D005702:Galantamine; D009538:Nicotine; D048448:Phenylcarbamates; D010830:Physostigmine; D011807:Quinolizines; D011978:Receptors, Nicotinic; D000068836:Rivastigmine; D012601:Scopolamine; D013619:Tacrine; C403531:nicotinic receptor alpha4beta2; C004712:cytisine; D000093843:Quinolizidine Alkaloids