title: Discovery & development of selective M3 antagonists for clinical use.
abstract: The treatment of airway obstructive disease may be improved by antimuscarinic agents which selectively block M1 and M3 receptors but do not inhibit prejunctional cholinergic autoreceptors which limit release of acetylcholine. Revatropate is a novel antimuscarinic agent which shows some 50-fold selectivity for M1 and M3 receptors in guinea pig trachea and rabbit vas deferens over the M2 subtype in atria. This selectivity profile was seen in vivo in anaesthetised guinea pigs and conscious dogs where bronchodilator activity was produced in the absence of any effect on heart rate. Revatropate, in contrast to the non-selective agent ipratropium, did not potentiate bronchoconstrictor responses induced by vagal nerve stimulation, indicating that inhibitory autoreceptors were still functional. Early clinical studies in COAD patients showed that inhaled revatropate was an effective bronchodilator which was well tolerated. Darifenacin differs from revatropate by showing selectivity for M3 receptors relative to both M2 and M1 subtypes. [3H] darifenacin had 5-fold higher affinity for the human m3 relative to m1 receptors while there was significantly reduced binding to m2, m4 and m5 receptors. The degree of selectivity in functional tissue preparations was even greater, with darifenacin showing 100-fold selectivity for the ileum M3 receptors over M2 receptors in atria and 30-fold over M1 receptors in rabbit vas deferens. Darifenacin was able to differentiate between M3 receptors in different tissues; although darifenacin was equipotent with atropine in the ileum and bladder, it was some 10-fold and 6-fold less potent at inhibiting muscarinic responses in the trachea and submandibular salivary gland respectively, relative to atropine. Studies in anaesthetised dogs confirmed this 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 studies are ongoing in urge incontinence and functional bowel disease which may confirm this selectivity profile.
authors.affiliation: Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, U.K.
authors.forename: V A
authors.initials: VA
authors.lastname: Alabaster
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000188:drug therapy; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: D001572:Benzofurans; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; C105222:revatropate; C101207:darifenacin