ANTIEMETIC EFFECTS OF N-3389 A NEWLY SYNTHESIZED 5-HT3 AND 5-HT4 RECEPTOR ANTAGONIST, IN FERRETS

The antiemetic activity of N-3389 zabicyclo[3,3,1]non-7-yl-1H-indazole -3-carboxamide dihydrochloride), a new 5-HT3 and 5-HT4 receptor antago nist, against cisplatin, cyclophosphamide- and copper sulfate-induced emesis was investigated using ferrets. We also examined the effects of these agents on abdominal afferent vagus nerve activity in anesthetiz ed ferrets. Both intraperitoneal (0.1-1.0 mg/kg) and oral (0.1-1.0 mg/ kg) administration of N-3389 produced dose-dependent antiemetic effect s. The time-course of cisplatin (10 mg/kg, i.p.)-induced emesis in ano ther group of ferrets paralleled the increase in abdominal afferent va gus nerve activity induced by cisplatin (10 mg/kg, i.p.) and was inhib ited by pretreatment with N-3389 (1.0 mg/kg, i.v.). Furthermore, the c isplatin (10 mg/kg, i.p.)-induced increase in abdominal afferent vagus nerve activity was markedly reduced by an additional injection of N-3 389 (0.1-1.0 mg/kg, i.v.) in a dose-dependent manner. The antiemetic e ffects exhibited by N-3389 are probably due to the inhibition of 5-HT3 and 5-HT4 receptors on the abdominal afferent vagus nerves.