1. Following our earlier observations that the
tachykinin NK1 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.