BINDING AND FUNCTIONAL-PROPERTIES OF HEXOCYCLIUM AND SILA-HEXOCYCLIUMDERIVATIVES TO MUSCARINIC RECEPTOR SUBTYPES

1 We have compared the binding properties of several hexocyclium and s ila-hexocyclium derivatives to muscarinic M(1) receptors (in rat brain , human neuroblastoma (NB-OK I) cells and calf superior cervical gangl ia), rat heart M(2) receptors, rat pancreas M(3) receptors and M(4) re ceptors in rat striatum, with their functional antimuscarinic properti es in rabbit vas deferens (M(1)/M(4)-like), guinea-pig atria (M(2)), a nd guinea-pig ileum (M(3)) muscarinic receptors.2 Sila-substitution (C /Si exchange) of hexocyclium (--> sila-hexocyclium) and demethyl-hexoc yclium (--> demethyl-sila-hexocyclium) did not significantly affect th eir affinities for muscarinic receptors. By contrast, sila-substitutio n of o-methoxy-hexocyclium increased its affinity 2 to 3 fold for all the muscarinic receptor subtypes studied. 3 The p-fluoro- and p-chloro -derivatives of sila-hexocyclium had lower affinities than the parent compound at the four receptor subtypes, in binding and pharmacological studies. 4 In binding studies, o-methoxy-sila-hexocyclium (M(1) = M(4 ) greater than or equal to M(3) greater than or equal to M(2)) had a m uch lower affinity than sila-hexocyclium for the four receptor subtype s, and discriminated the receptor subtypes more poorly than sila-hexoc yclium (M(1) = M(3) > M(4) > M(2)). This is in marked contrast with th e very clear selectivity of o-methoxy-sila-hexocyclium fdr the prejunc tional M(1)/M(4)-like heteroreceptors in rabbit vas deferens. 5 The te rtiary amines demethyl-hexocyclium, demethyr-sila-hexocyclium and deme thyl-o-methoxy-sila-hexocyclium had 10 to 30 fold lower affinities tha n the corresponding quaternary ammonium derivatives.