1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives.

Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.