title: 5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370.
abstract: The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-)-N-[1-methyl-4-(3-methyl-benzyl)hexahydro-1H-1,4-diazepin-6- yl]-1H- indazole-3-carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthetized rats, DAT-582 antagonized 2-methyl-5-HT-induced bradycardia with an ED50 value of 0.25 microgram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i.v.)-induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.
authors.affiliation: Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: H
authors.initials: H
authors.lastname: Omoya
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001919:Bradycardia / Q000139:chemically induced / Q000517:prevention & control; D002945:Cisplatin / Q000037:antagonists & inhibitors; D005289:Ferrets; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D012702:Serotonin Antagonists; D013237:Stereoisomerism; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D001381:Azepines; D007191:Indazoles; D012702:Serotonin Antagonists; C073385:DAT 582; D002945:Cisplatin