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

Few muscarinic antagonists differentiate between the M-4 and M-2 muscarinic receptors. In a structure-activity study, aimed at discovering leads for t he development of a M-4 muscarinic receptor-selective antagonist, we have s ynthesized and tested at cloned muscarinic receptors the binding of a group of dioxolane- or oxadiazole-dialkyl amines, and compared them to our compo und 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 rece ptors than at M-2 receptors (similar to 3- and 4-fold, respectively). The d ioxolane 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 t hey are not M-4-selective. The M-4/M-2 relative selectivities of some of ou r compounds are similar to the better hexahydrosiladifenidol derivatives, a nd may provide some important structural clues for the development of poten t and selective M-4 antagonists. (C) 2000 Elsevier Science Ltd. Ail rights reserved.