title: Serotonin (5-HT)3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives against 5-HT-induced bradycardia in anesthetized rats.
abstract: We investigated the mode of the 5-HT3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives, YM060, YM114 (KAE-393), YM-26103-2 and YM-26308-2, against 5-HT-induced transient bradycardia in anesthetized rats. Results were compared with those of ondansetron and granisetron. YM060 (0.03-0.1 microgram/kg, i.v.), YM114 (0.03-0.3 microgram/kg, i.v.), YM-26103-2 (0.01-0.03 microgram/kg, i.v.), YM-26308-2 (0.01-0.03 microgram/kg, i.v.) and granisetron (0.3-3 micrograms/kg, i.v.) displaced the 5-HT dose-response curve to the right, with apparent DR2 values of 0.068, 0.068, 0.019, 0.011 and 0.69 microgram/kg, i.v., respectively. Higher doses of these compounds inhibited 5-HT-induced bradycardia with a reduced maximal response. In contrast, ondansetron displaced the 5-HT dose-response curve to the right without affecting the maximal response. Judged by the apparent DR2 values, YM060, YM114, YM-26103-2 and YM-26308-2 were approximately 13, 13, 50 and 79 times more potent than ondansetron, respectively, whereas granisetron was equipotent to ondansetron. Single i.v. doses of YM060 and granisetron inhibited 5-HT-induced bradycardia significantly longer than ondansetron. Moreover, inhibitory effects of p.o. doses of YM060 (3 micrograms/kg), YM114 (80 micrograms/kg), YM-26103-2 (12 micrograms/kg), YM-26308-2 (5 micrograms/kg) and granisetron (250 micrograms/kg) on the von Bezold-Jarisch reflex lasted for 3-6 hr, whereas ondansetron (700 micrograms/kg, p.o.) antagonized 5-HT3 receptors for only 1 hr. In isolated guinea pig colon, the inhibitory effect of YM-compounds on 5-HT-induced contraction persisted significantly longer than those of ondansetron and granisetron after washout of the bath containing compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Neuroscience & Gastrointestinal Research Laboratory, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamano
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: Ito
authors.forename: H
authors.initials: H
authors.lastname: Yuki
authors.forename: R
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: K
authors.initials: K
authors.lastname: Miyata
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017829:Granisetron / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007212:Indolizines / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D017294:Ondansetron / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000633:toxicity; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D017829:Granisetron; D007212:Indolizines; D017294:Ondansetron; D012701:Serotonin; D012702:Serotonin Antagonists; C085986:YM 114; C091097:YM 26103-2; C091098:YM 26308-2; C071315:ramosetron