DISCOVERY AND DEVELOPMENT OF SELECTIVE M(3) ANTAGONISTS FOR CLINICAL USE

The treatment of airway obstructive disease may be improved by antimus carinic agents which selectively block M(1) and M(3) receptors but do not inhibit prejunctional cholinergic autoreceptors which limit releas e of acetylcholine. Revatropate is a novel antimuscarinic agent which shows some 50-fold selectivity for M(1) and M(3) receptors in guinea p ig trachea and rabbit vas deferens over the M(2) subtype in atria. Thi s selectivity profile was seen in vivo in anaesthetised guinea pigs an d conscious dogs where bronchodilator activity was produced in the abs ence of any effect on heart rate. Revatropate, in contrast to the non- selective agent ipratropium, did not potentiate bronchoconstrictor res ponses induced by vagal nerve stimulation, indicating that inhibitory autoreceptors were still functional. Early clinical studies in COAD pa tients showed that inhaled revatropate was an effective bronchodilator which was well tolerated. Darifenacin differs from revatropate by sho wing selectivity for M(3) receptors relative to both M(2) and M(1) sub types. [H-3] darifenacin had 5-fold higher affinity for the human m3 r elative to m1 receptors while there was significantly reduced binding to m2, m4 and m5 receptors. The degree of selectivity in functional ti ssue preparations was even greater, with darifenacin showing 100-fold selectivity for the ileum M(3) receptors over M(2) receptors in atria and 30-fold over M(1) receptors in rabbit vas deferens. Darifenacin wa s able to differentiate between M(3) receptors in different tissues; a lthough darifenacin was equipotent with atropine in the ileum and blad der, it was some 10-fold and 6-fold less potent at inhibiting muscarin ic responses in the trachea and submandibular salivary gland respectiv ely, relative to atropine. Studies in anaesthetised dogs confirmed thi s selectivity profile. Thus darifenacin inhibited responses of the gut and bladder to cholinergic stimulation without affecting heart rate. Salivary gland responses were inhibited at doses some 6-10 fold higher than those required to inhibit gut and bladder responses. Clinical st udies are ongoing in urge incontinence and functional bowel disease wh ich may confirm this selectivity profile.