Synthesis, Affinity Profile and Functional Activity of Potent Chiral Muscarinic Antagonists with a Pyrrolidinylfuran Structure

Starting from the structure of previously studied muscarinic agonists, characterized by a pyrrolidinylfurane scaffold, a new series of muscarinic antagonists was synthesized by substituting the 5-position of the furane cycle with bulky hydrophobic groups. Both tertiary amines and the corresponding iodomethyl derivatives were obtained and studied. All the new compounds show high affinity toward cloned human muscarinic m1-m5 receptors expressed in CHO cells and behave as competitive antagonists on classical models of muscarinic receptors. The diastereoisomeric mixture of the most affinitive compound of the series has been resolved into the four optical isomers by chiral HPLC and the relative and absolute configuration of the compounds obtained has been established by means of a combined strategy based on X-ray crystallography and chiroptical techniques. Although being fairly potent in general, the compounds show only modest subtype selectivity with the exception of 2a and 6a that in functional assays present a clear-cut selectivity for the muscarinic receptors present in rabbit vas deferens.