title: DAT-582, a novel serotonin3 receptor antagonist, is a potent and long-lasting antiemetic agent in the ferret and dog.
abstract: The antiemetic effects of a novel serotonin3 receptor antagonist, DAT-582 [(6R)-(-)-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4- diazepin-6-yl]-1H-indazole-3-carboxamide dihydrochloride] were compared with those of the existing serotonin3 receptor antagonists, ondansetron and granisetron, in experimental animals. In ferrets, DAT-582 (0.003-0.1 mg/kg i.v. twice) dose-relatedly prolonged the latency to the first emetic episode and decreased the number of emetic episodes induced by cisplatin (10 mg/kg i.v.). DAT-582 was more potent than ondansetron or granisetron in inhibiting the emesis. The emesis induced by cyclophosphamide (150 mg/kg i.v.), doxorubicin (15 mg/kg i.v.) or combination of cisplatin (3.3 mg/kg i.v.), cyclophosphamide (50 mg/kg i.v.) and doxorubicin (5 mg/kg i.v.) was also inhibited by DAT-582 (0.1 mg/kg i.v., twice). When administered 2 hr before cisplatin in ferrets, DAT-582 decreased markedly the number of emetic episodes induced by cisplatin at 0.1 mg/kg i.v., whereas ondansetron and granisetron were without effect even at 0.3 mg/kg i.v. DAT-582 (0.1 mg/kg i.v.), when administered in the ferrets which were vomiting after cisplatin, immediately and almost completely blocked the subsequent emesis. Furthermore, DAT-582 (0.1 mg/kg i.v.) completely inhibited the cisplatin (3 mg/kg i.v.)-induced emesis for 24 hr after cisplatin in three of five dogs. In addition, DAT-582, at 0.3 and 1 mg/kg, p.o., inhibited the cisplatin-induced emesis in dogs. However, DAT-582, even at 3 mg/kg s.c., did not inhibit the apomorphine (0.3 mg/kg,, s.c.)-induced emesis in dogs, or the nicotine-, copper sulfate- or motion stimulus-induced emesis in the house musk shrew, Suncus Murinus.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: H
authors.initials: H
authors.lastname: Omoya
authors.forename: T
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity; D003300:Copper / Q000633:toxicity; D019327:Copper Sulfate; D004285:Dogs; D005260:Female; D005289:Ferrets; D005746:Gastric Emptying / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000633:toxicity; D017294:Ondansetron; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012788:Shrews
chemical_list: D000932:Antiemetics; D001381:Azepines; D007093:Imidazoles; D007191:Indazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C073385:DAT 582; D017294:Ondansetron; D009538:Nicotine; D003300:Copper; D019327:Copper Sulfate; D002945:Cisplatin