THE BROAD-SPECTRUM ANTIEMETIC ACTIVITY OF THE NOVEL NONPEPTIDE TACHYKININ NK1 RECEPTOR ANTAGONIST GR203040

1 Following our earlier observations that the tachykinin NK, receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have e xamined the anti-emetic effects of a more potent and novel NK1 recepto r antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2 In ferrets, GR203040 (0.1 mg kg(-1) s.c. or i.v.) is effective against emesis induced by radiat ion, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morp hine. 3 In animals in which emesis had been established with cisplatin , GR203040 (1 mg kg(-1) s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR20304 0 whilst saline-treated animals continued to vomit. 4 GR203040 (0.1 mg kg(-1) s.c.) retains anti-emetic efficacy in the ferret, even when gi ven as a 6 h pretreatment, indicating that this compound has a long du ration of action. The compound is also effective orally at the same do se, when given as a 90 min pretreatment. 5 GR203040 (0.1 mg kg(-1) i.v .) is fully effective against ipecacuanha-induced emesis in the dog. 6 GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitud e greater than those shown to be effective against cisplatin in the fe rret. 7 In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observe d in three species, suggests that this compound is worthy of clinical investigation.