Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M3-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Binding and functional affinities of the muscarinic acetylcholine (mACh) receptor antagonists darifenacin, tolterodine, oxybuty-nin, and atropine were assessed in Chinese hamster ovary (CHO) cells expressing the human recombinant M2 (CHO-m2) or M3 (CHO-m3) receptors, and in guinea pig bladder and submandibular gland. In [N-methyl-3H]scopolamine methyl chloride binding studies in CHO cells, darifenacin displayed selectivity (14.8-fold) for the M3 versus M2 mACh receptor subtype. Oxybutynin was nonselective, whereas atropine and tolterodine were weakly M2-selective (5.1- and 6.6-fold, re-spectively). Antagonist functional affinity estimates were deter-mined by the inhibition of agonist-induced [3H]inositol phos-phate accumulation in CHO-m3 cells and antagonism of the agonist-induced inhibition of forskolin-stimulated cyclic AM