Synthesis and structure-activity relationships in a set of new antimuscarinic agents

Three quaternary ammonium salts (4-6), related to muscarine and muscarone, were designed as antimusearinic agents and synthesized by means of a iodoet herification reaction carried out on an unsaturated diol. The structurally related furanone 7 together with isoxazoles 10-12 and Delta (2)-isoxazoline s 14 and 15 were in turn obtained via 1,3-dipolar cyloaddition of benzoylfo rmonitrile oxide to suitable alkynes and alkenes. The new derivatives were tested in vitro for antimuscarinic activity at guinea pig atria (M-2) and a t two different M-3 tissue preparations (rat jejunum and guinea pig bladder ). Selected compounds were also examined for binding activity at M-1, M-2, and M-3 muscarinic receptors. The major part of the derivatives under study behaved as highly potent, though non selective, muscarinic antagonists. We propose selected geometrical parameters capable of predicting the selectiv ity of new antagonists for M-2 versus M-3 receptors.