Design and synthesis of ether analogues as potent and selective M2 muscarinic receptor antagonists

Novel, selective M2 muscarinic antagonists, which replace the metabolically labile styrenyl moiety of the prototypical M2 antagonist 1 with an ether linkage, were synthesized. A detailed SAR study in this class of compounds has yielded highly active compounds that showed M2Ki values of <1.0 nM and >100-fold selectivity against M1, M3, and M5 receptors.