Interactions of piperidine derivatives with the nicotinic cholinergic receptor complex from Torpedo electric organ

The interactions of eight piperidine derivatives with nicotinic receptor complexes from Torpedo californica electric organ were studied using [125I] alpha-bungarotoxin [( 125I]BGT) as a probe for the acetylcholine binding site and [3H]perhydrohistrionicotoxin [( 3H]H12-HTX) as a probe for a site associated with the receptor-gated ion channel. Cis- and trans-2-methyl-6-n-undecanyl piperidines (MUP), major constituents of fire ant venom, had a high-affinity for [3H]H12-HTX binding sites (Ki = 0.08-0.24 microM), but had no affect on receptor binding. MUP affinity for [3H]H12-HTX binding sites was approximately doubled in the presence of 1 microM carbamylcholine. Introduction of a 2'-hydroxyl group to the undecanyl side channel had little effect on activity of the alkaloid. The analog 2,6- (but not 3,5-) dimethylpiperidine was a moderately active inhibitor of [3H]H12-HTX binding (Ki = 8.8 microM). 2-Methylpiperidine was considerably less active (Ki = 600 microM), although it was more potent than either 3- or 4-methylpiperidine. The affinities of 2,6-dimethylpiperidine and 2-methylpiperidine for [3H]H12-HTX binding sites were decreased in the presence of 1 microM carbamylcholine. Carbamylcholine affinity for the receptor was increased by up to 7 fold in the presence of 10 and 32 microM MUP, but was decreased in the presence of 2,6-dimethylpiperidine and 2-methylpiperidine. The cis- and trans-isomers of MUP were equipotent in producing each of its effects. In these actions, MUP resembles a variety of other compounds derived from 2,6-disubstituted piperidines, including histrionicotoxins, gephyrotoxins and pumiliotoxins.(ABSTRACT TRUNCATED AT 250 WORDS)