DAT-582, a novel serotonin3 receptor antagonist, is a potent and long-lasting antiemetic agent in the ferret and dog.

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)