THE STRUCTURE OF THE NEURONAL NICOTINIC A CETYLCHOLINE-RECEPTOR ION-CHANNEL AS ESTIMATED ON THE BASIS OF THE STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF OPEN-CHANNEL BLOCKING-DRUGS

To investigate the topography of the bis-cationic blocking agent bindi ng site of the neuronal nicotinic acetylcholine receptor ion channel, the structure-activity relationships were studied for pentaethonium an d pentamethonium derivatives (56 compounds) with the cationic groups o f different degrees of substitution. The blocking effects of the compo unds on ganglionic transmission were studied in cat superior ganglion in situ and in pieces of the guinea-pig small intestine. Equilibrium c onformations of each compound were calculated by the molecular mechani cs method. The analysis of the conformation-activity relationships for the bis-cationic blocking drugs has yielded a model of the binding si te of the ion channel. The ion channel of the neuronal nicotinic acety lcholine receptor was suggested to be funnel-shaped with two anionic s ites in its tapering. The dimensions of the narrow profile of the ion channel in the region of the first anionic site correspond to a rectan gle 6.1 . 8.3 Angstrom. The dimensions of the narrow profile in the re gion of the second anionic site correspond to a rectangle 5.5 x 6.3 An gstrom. These sites are separated by the distance of 7.5 Angstrom (pen tamethylene chain in the fully extended all-trans conformation). Quate rnary ammonium groups of the bis-cationic blockers were fixed to a gre ater extent on the second anionic site.