A novel 5-HT3 receptor agonist, YM-31636, increases gastrointestinal motility without increasing abdominal pain.
We examined the effects of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate), a novel 5-HT3 receptor agonist, on gastrointestinal functions including visceral pain reflex in rats. Injection of YM-31636 increased the number of fecal pellets. This effect was completely inhibited by ramosetron, a 5-HT3 receptor antagonist. YM-31636 also increased the intracolonic pressure measured in both conscious and anesthetized rats. In isolated distal colon, YM-31636 increased the short-circuit current response. This effect was abolished by ramosetron. Both the maximal response and the potency of YM-31636 were weaker than those of other 5-HT3 receptor agonists. In two visceral pain reflex models, YM-31636 neither changed the magnitude of pressor response to colonic distension in anesthetized rats nor affected the visceromotor threshold to colorectal distension in conscious rats. In conclusion, YM-31636 facilitated defecation without increasing visceral pain. Consequently, 5-HT3 receptor agonists like YM-31636 would be promising in the treatment of chronic constipation.
Kiso
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Ibaraki 305-8585, Tsukuba, Japan. kiso@yamanouchi.co.jp
Ito
H
H
Miyata
K
K
Kamato
T
T
Naitoh
Y
Y
Iwaoka
K
K
Yamaguchi
T
T
D015746:Abdominal Pain; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000294:innervation; D003672:Defecation / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D011312:Pressure; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012020:Reflex, Abdominal / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014867:Water / Q000378:metabolism
C419869:2-(1H-imidazol-4-ylmethyl)-8H-indeno(1,2-d)thiazole; D001562:Benzimidazoles; D011758:Pyrroles; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D014867:Water; C071315:ramosetron