PRECLINICAL AND CLINICAL-PHARMACOLOGY OF SELECTIVE MUSCARINIC M(3) RECEPTOR ANTAGONISTS

Muscarinic M(3) receptor antagonists have therapeutic potential for the treatment of disorders associated with altered smooth muscle contractility or tone. These include irritable bowel syndrome (IBS), chronic obstructive airways disease (GOAD) and urinary incontinence. Zamifenacin is a potent muscarinic receptor antagonist on the guinea pig ileum (pA(2) value 9.27) with selectivity over M(2) receptors in the atria (135-fold) and M(1)/M(4) receptors in the rabbit vas deferens (78-fold). In addition, zamifenacin had lower affinity for the M(3) receptor in the salivary gland (pKi 7.97). In animals, zamifenacin potently inhibited gut motility in the absence of cardiovascular effects and with selectivity over inhibition of salivary secretion. In healthy volunteers, zamifenacin inhibited small and large bowel motility and increased the rate of gastric emptying over a dose range which was associated with minimal anticholinergic side effects. These data show that zamifenacin, a selective muscarinic M(3) receptor antagonist, was well tolerated in man and was efficacious as an inhibitor of gut motility. Further studies in patients are required with muscarinic M(3) receptor antagonists to confirm efficacy against symptoms in diseases associated with altered smooth muscle contractility.