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

Muscarinic M(3) receptor antagonists have therapeutic potential for th e treatment of disorders associated with altered smooth muscle contrac tility or tone. These include irritable bowel syndrome (IBS), chronic obstructive airways disease (GOAD) and urinary incontinence. Zamifenac in 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 inhib ited gut motility in the absence of cardiovascular effects and with se lectivity over inhibition of salivary secretion. In healthy volunteers , zamifenacin inhibited small and large bowel motility and increased t he rate of gastric emptying over a dose range which was associated wit h minimal anticholinergic side effects. These data show that zamifenac in, a selective muscarinic M(3) receptor antagonist, was well tolerate d in man and was efficacious as an inhibitor of gut motility. Further studies in patients are required with muscarinic M(3) receptor antagon ists to confirm efficacy against symptoms in diseases associated with altered smooth muscle contractility.