Anti-emetic activity of the novel nonpeptide tachykinin NK1 receptor antagonist ezlopitant (CJ-11,974) against acute and delayed cisplatin-induced emesis in the ferret.

The anti-emetic effects of a novel tachykinin NK1 receptor antagonist, ezlopitant ((2S,3S-cis)-2-diphenylmethyl)-N-1(2-methoxy, 5-isopropylphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine), were investigated in ferrets. Ezlopitant inhibited [H-3]substance P ([H-3]SP) binding to the human, guinea pig, ferret and gerbil NK1 receptors (K-i = 0.2, 0.9. 0.6 and 0.5 nmol/l, respectively), but had no affinity to NK2 and NK3 receptors up to 1 mumol/l. Ezlopitant also inhibited SP-induced contraction of guinea pig trachea with a pA(2) value of 7.8, but had no effects on the baseline tension and maximum contractile response. In ferrets, ezlopitant, either orally (0.03-3 mg/kg) or subcutaneously (0.3-3 mg/kg), prevented acute retching and vomiting responses induced by intraperitoneal injection of cisplatin (10 mg/kg). In addition, repeated subcutaneous injection of ezlopitant significantly inhibited delayed retching and vomiting responses that occurred in ferrets treated with the lower dose of cisplatin (5 mg/kg, i.p.). Ezlopitant (0.1-1 mg/kg, s.c.) also produced a dose-dependent inhibition of hindpaw tapping induced by intracerebroventricular injection of [Sar(9),Met(O-2)(11)]SP in gerbils, which is known to be mediated by NK1 receptors in the brain. These findings indicate that ezlopitant is a potent and selective NK1 receptor antagonist, and that it inhibits both acute and delayed emetic reactions induced by cisplatin in ferrets via acting on NK1 receptors in the central nervous system. Copyright (C) 2002 S. Karger AG, Basel.