Pre-clinical and clinical pharmacology of selective muscarinic M3 receptor antagonists.
Muscarinic M3 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 (COAD) and urinary incontinence. Zamifenacin is a potent muscarinic receptor antagonist on the guinea pig ileum (pA2 value 9.27) with selectivity over M2 receptors in the atria (135-fold) and M1/M4 receptors in the rabbit vas deferens (78-fold). In addition, zamifenacin had lower affinity for the M3 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 M3 receptor antagonist, was well tolerated in man and was efficacious as an inhibitor of gut motility. Further studies in patients are required with muscarinic M3 receptor antagonists to confirm efficacy against symptoms in diseases associated with altered smooth muscle contractility.
Wallis
R M
RM
Department Discovery Biology, Pfizer Central Research, Sandwich Kent, United Kingdom.
D000818:Animals; D016275:Atrial Function; D001285:Atropine / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004025:Dicyclomine / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D004149:Dioxoles; D018727:Muscarinic Antagonists; D010880:Piperidines; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D004025:Dicyclomine; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C097932:zamifenacin