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 antimuscarinic agents and synthesized by means of a iodoetherification reaction carried out on an unsaturated diol. The structurally related furanone 7 together with isoxazoles 10-12 and Δ2-isoxazolines 14 and 15 were in turn obtained via 1,3-dipolar cyloaddition of benzoylformonitrile oxide to suitable alkynes and alkenes. The new derivatives were tested in vitro for antimuscarinic activity at guinea pig atria (M2) and at two different M3 tissue preparations (rat jejunum and guinea pig bladder). Selected compounds were also examined for binding activity at M1, M2, and M3 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 selectivity of new antagonists for M2 versus M3 receptors.