title: Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation.
abstract: YM114 (KAE-393), (R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole hydrochloride, is a derivative of YM060, a potent 5-HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depolarization of the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) failed to inhibit 5-HT-induced bradycardia, implying that it does not possess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint stress-, 5-HT- and TRH-induced increases in fecal pellet output, and restraint stress- and 5-HT-induced diarrhea in rats and mice (ED50 = 6.9, 72.5, 154.6, 9.7 and 52.4 micrograms/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine.
authors.affiliation: Neuroscience and Gastrointestinal Research Laboratories, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Yamano
authors.forename: K
authors.initials: K
authors.lastname: Hidaka
authors.forename: T
authors.initials: T
authors.lastname: Kamato
authors.forename: A
authors.initials: A
authors.lastname: Nishida
authors.forename: H
authors.initials: H
authors.lastname: Yuki
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002368:Castor Oil; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003672:Defecation / Q000187:drug effects*; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D015232:Dinoprostone / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000493:pharmacokinetics; D007211:Indoles / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009620:Nodose Ganglion / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D013315:Stress, Psychological / Q000523:psychology*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014287:Trimebutine / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D007093:Imidazoles; D007211:Indoles; D012702:Serotonin Antagonists; C059068:GR 65630; C085986:YM 114; D012701:Serotonin; D013973:Thyrotropin-Releasing Hormone; D002368:Castor Oil; D015232:Dinoprostone; D014287:Trimebutine