Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets.

Abstract

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.

• Authors: M Minami, T Endo, H Tamakai, T Ogawa, N Hamaue, M Hirafuji, Y Monma, M Yoshioka, K Hagihara
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 321 Issue 3 Pg. 333-42 (Mar 05 1997) ISSN: 0014-2999 [Print] Netherlands
• PMID: 9085045 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiemetics
• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Emetics
• Indazoles
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• Serotonin Antagonists
• Receptors, Serotonin, 5-HT4
• Serotonin
• 5-Methoxytryptamine
• 2-methyl-5-HT
• Cyclophosphamide
• Copper Sulfate
• N 3389
• Cisplatin

Topics

• 5-Methoxytryptamine (pharmacology)
• Animals
• Antiemetics (pharmacology)
• Antineoplastic Agents (toxicity)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cisplatin (toxicity)
• Copper Sulfate (toxicity)
• Cyclophosphamide (toxicity)
• Emetics (toxicity)
• Ferrets
• Indazoles (pharmacology)
• Male
• Receptors, Serotonin (drug effects)
• Receptors, Serotonin, 5-HT3
• Receptors, Serotonin, 5-HT4
• Serotonin (analogs & derivatives, pharmacology)
• Serotonin Antagonists (pharmacology)
• Vagus Nerve (drug effects, physiology)
• Vomiting (chemically induced, drug therapy)