Minami M, Endo T, Tamakai H, Ogawa T, Hamaue N, Hirafuji M, Monma Y, Yoshioka M, Hagihara K
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan.
Eur J Pharmacol. 1997 Mar 5;321(3):333-42. doi: 10.1016/s0014-2999(96)00974-0.
The antiemetic activity of N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1 H-indazole-3-carboxamide dihydrochloride), a new 5-HT3 and 5-HT4 receptor antagonist, 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 anesthetized 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 effects. The time-course of cisplatin (10 mg/kg, i.p.)-induced emesis in another group of ferrets paralleled the increase in abdominal afferent vagus nerve activity induced by cisplatin (10 mg/kg, i.p.) and was inhibited by pretreatment with N-3389 (1.0 mg/kg, i.v.). Furthermore, the cisplatin (10 mg/kg, i.p.)-induced increase in abdominal afferent vagus nerve activity was markedly reduced by an additional injection of N-3389 (0.1-1.0 mg/kg, i.v.) in a dose-dependent manner. The antiemetic effects exhibited by N-3389 are probably due to the inhibition of 5-HT3 and 5-HT4 receptors on the abdominal afferent vagus nerves.
新型5-HT3和5-HT4受体拮抗剂N-3389（内-3,9-二甲基-3,9-二氮杂双环[3,3,1]壬-7-基-1H-吲唑-3-甲酰胺二盐酸盐）对顺铂、环磷酰胺和硫酸铜诱发雪貂呕吐的止吐活性进行了研究。我们还研究了这些药物对麻醉雪貂腹部传入迷走神经活动的影响。腹腔注射（0.1-1.0mg/kg）和口服（0.1-1.0mg/kg）N-3389均产生剂量依赖性止吐作用。另一组雪貂中，顺铂（10mg/kg，腹腔注射）诱发呕吐的时间进程与顺铂（10mg/kg，腹腔注射）诱发的腹部传入迷走神经活动增加平行，且被N-3389（1.0mg/kg，静脉注射）预处理所抑制。此外，额外注射N-3389（0.1-1.0mg/kg，静脉注射）可使顺铂（10mg/kg，腹腔注射）诱发的腹部传入迷走神经活动增加以剂量依赖性方式显著降低。N-3389表现出的止吐作用可能是由于抑制了腹部传入迷走神经上的5-HT3和5-HT4受体。
