Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo.
We investigated the effects of YM905 [(+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate], a new orally active muscarinic M3-receptor antagonist, on bowel dysfunction in vivo using experimental models that reproduce the symptoms present in irritable bowel syndrome (IBS). YM905 potently inhibited restraint stress-induced fecal pellet output in fed rats (ED50: 4.0 mg/kg) and diarrhea in fasted rats (ED50: 1.7 mg/kg), with similar potencies to the inhibition of bethanechol-, neostigmine- and nicotine-induced fecal pellet output in rats (ED50: 3.3, 7.9 and 4.5 mg/kg, respectively). YM905 also inhibited 5-hydroxytryptamine (5-HT)-, prostaglandin E2- and castor oil-induced secretory diarrhea in mice (ED50: 5.5, 14 and 6.3 mg/kg, respectively), but showed no significant effect on cholera toxin-induced intestinal secretion in mice. In addition, YM905 (3, 10 mg/kg) reversed morphine-decreased postprandial defecation in ferrets, a model of spastic constipation, whereas remosetron, a 5-HT3-receptor antagonist, was not effective. The mode of YM905 action was similar to that of darifenacin, a selective M3-receptor antagonist, with equivalent potencies. By contrast, propantheline, an antimuscarinic drug that has been used for IBS, was much less potent. These results show that YM905 ameliorates a wide spectrum of bowel dysfunctions through the blockade of M3 receptors, suggesting its therapeutic potential for treating IBS.
Kobayashi
S
S
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan. kobayashi.seiji@yamanouchi.co.jp
Ikeda
K
K
Suzuki
M
M
Yamada
T
T
Miyata
K
K
D000818:Animals; D018723:Bethanechol / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D003109:Colonic Diseases, Functional / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000209:etiology / Q000517:prevention & control; D015232:Dinoprostone / Q000502:physiology; D004195:Disease Models, Animal; D007422:Intestines / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009388:Neostigmine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology; D000069464:Solifenacin Succinate; D013312:Stress, Physiological / Q000150:complications; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; D018723:Bethanechol; D012701:Serotonin; D009388:Neostigmine; D009538:Nicotine; D002772:Cholera Toxin; D015232:Dinoprostone; D000069464:Solifenacin Succinate