Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets.
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.
Minami
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan.
Endo
T
T
Tamakai
H
H
Ogawa
T
T
Hamaue
N
N
Hirafuji
M
M
Monma
Y
Y
Yoshioka
M
M
Hagihara
K
K
D008735:5-Methoxytryptamine / Q000494:pharmacology; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity; D019327:Copper Sulfate / Q000633:toxicity; D003520:Cyclophosphamide / Q000633:toxicity; D004639:Emetics / Q000633:toxicity; D005289:Ferrets; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy*
D000932:Antiemetics; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004639:Emetics; D007191:Indazoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D008735:5-Methoxytryptamine; C045918:2-methyl-5-HT; D003520:Cyclophosphamide; D019327:Copper Sulfate; C092823:N 3389; D002945:Cisplatin