MUSCARINIC AGONISTS - SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF BICYCLIC ISOXAZOLE ESTER BIOISOSTERES OF NORARECOLINE

thyl-5,6,7,8-tetrahydra-4H-isoxazolo[4,5-c]azepine (O,8-di-Me-THAO, 2c ) and (RS)-8-methyl-3- loxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azep ine (8-Me-O-propargyl-THAO, 2d) have been synthesized and evaluated as muscarinic receptor ligands in receptor binding assays and in in vitr o functional assays. The corresponding compounds without methyl groups at C-8, ie O-Me THAO (2a) and O-propargyl-THAO (2b), have previously been shown to exhibit muscarinic agonistic profiles with very little d iscrimination between M(1)- and M(2)-receptor sites. Based on function al assays, 2c and 2d were found to be less efficacious than 2a and 2b, respectively, and 2d proved to be an M(1)-selective partial agonist. The-affinity and M(1) efficacy of 2c and 2d were comparable to those o f the corresponding six-membered ring analogues, methyl-4,5,6,7-tetrah ydro-isoxazolo[4,5-c]pyridine (O,7-di-Me-THPO, 1c) and rgyloxy-4,5,6,7 -tetrahydroisoxazolo[4,5-c]pyridine (7-Me-O-propargyl-THPO, 1d). Howev er, neither compound 1c nor compound 1d-displayed M(1) selectivity. In summary, within this class of bicyclic muscaninic agonists, replaceme nt of 3-methoxy by 3-propargyloxy groups generally increases muscarini c affinity without effecting the efficacy at M(1) receptors significan tly. Introduction of a methyl group into the saturated ring, at the po sition alpha to the C-5 of the isoxazole ring (alpha-position) lead to compounds exerting lower efficacy and, in the case of compound 2d, an increased selectivity with respect to M(1) agonism.