Investigation of the effects of YM-31636, a novel 5-HT3 receptor agonist, on defecation in normal and constipated ferrets.
We examined the effects of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate), a newly synthesized 5-HT(3) receptor agonist, on defecation in normal and constipated ferrets, and evaluated it as an agent against constipation. YM-31636 facilitated defecation without inducing diarrhea or emetic episodes. This effect occurred within 1 h after oral administration, mostly within 30 min, whereas sodium picosulfate, a widely used laxative, tended to increase the frequency of defecation for several hours with much lower peak incidence than that of YM-31636, and induced diarrhea. UK14304 (brimonidine), an alpha2 receptor agonist, and morphine reduced the frequency of defecation and YM-31636 restored it. These effects of YM-31636 were antagonized by ramosetron, a 5-HT(3) receptor antagonist. These results suggest that YM-31636 could be promising in the treatment of constipation. Because of an early and reliable onset of action compared with sodium picosulfate, YM-31636 could make it easier to control the time of defecation.
Ito
H
H
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Ibaraki 305-8585, Tsukuba, Japan. ito@yamanouchi.co.jp
Kiso
T
T
Yuki
H
H
Naitoh
Y
Y
Miyata
K
K
Iwaoka
K
K
Yamaguchi
T
T
D000818:Animals; D002951:Citrates; D003248:Constipation / Q000503:physiopathology*; D003672:Defecation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005243:Feces; D005289:Ferrets; D008297:Male; D009325:Nausea / Q000139:chemically induced; D009942:Organometallic Compounds; D010847:Picolines / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced; D014867:Water / Q000378:metabolism
C419869:2-(1H-imidazol-4-ylmethyl)-8H-indeno(1,2-d)thiazole; D002951:Citrates; D009942:Organometallic Compounds; D010847:Picolines; D011758:Pyrroles; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D014867:Water; C005701:picosulfate sodium