Design, synthesis and binding at cloned muscarinic receptors of N-[5-(1'-substituted-acetoxymethyl)-3-oxadiazolyl] and N-[4-(1'-substituted-acetoxymethyl)-2-dioxolanyl] dialkyl amines.

Abstract Few muscarinic antagonists differentiate between the M 4 and M 2 muscarinic receptors. In a structure–activity study, aimed at discovering leads for the development of a M 4 muscarinic receptor-selective antagonist, we have synthesized and tested at cloned muscarinic receptors the binding of a group of dioxolane- or oxadiazole-dialkyl amines, and compared them to our compound 1 , which contains the furan nucleus. Although none of these agents were particularly potent at M 4 receptors ( K d values were typically 30–70 nM), furan derivatives (−)1 and (+)1 were significantly more potent at M 4 receptors than at M 2 receptors (∼3- and 4-fold, respectively). The dioxolane derivatives 12b and 12c were more than 10-fold selective for the M 4 versus the M 2 receptors, while the dioxolane derivative 12e was 15-fold more potent at M 4 receptors than for M 2 receptors. However, these agents bound to M 3 receptors with potencies like that for the M 4 receptor, so they are not M 4 -selective. The M 4 /M 2 relative selectivities of some of our compounds are similar to the better hexahydrosiladifenidol derivatives, and may provide some important structural clues for the development of potent and selective M 4 antagonists.