The broad-spectrum anti-emetic activity of the novel non-peptide 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 examined the anti-emetic effects of a more potent and novel NK1 receptor 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 radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 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 GR203040 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 given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, 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 magnitude greater than those shown to be effective against cisplatin in the ferret. 7 In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.