The effect of CP‐99994 on the responses to provocative motion in the cat

The NK1 receptor antagonist CP-99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat. CP-99994 displaced [3H]-substance P from cat cortex with IC50 of 0.52±0.08 nm. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h. Subcutaneous administration of CP-99994 inhibited motion-induced vomiting in the cat with an ED50 of 144 μg kg−1 but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 μg kg−1. The antiemetic effect of CP-99994 can be attributed to antagonism of the NK1 receptor because its enantiomer, CP-100,263, which is 900 fold weaker as an NK1 antagonist, had no effects on any response to provocative motion. The inhibitory effect of CP-99994 on motion-induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours. An investigation into whether the failure of CP-99994 to alter the epiphenomena will also predict a lack of anti-nausea effects in man will provide critical information on the neural organization of the emetic reflex. British Journal of Pharmacology (1997) 120, 116–120; doi:10.1038/sj.bjp.0700888