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

Abstract

The anti-emetic effects of a novel tachykinin NK₁ receptor antagonist, ezlopitant ((2S,3S-cis)-2-diphenylmethyl)- N--1-azabicyclo- [2.2.2]octan-3-amine), were investigated in ferrets. Ezlopitant inhibited [³H]substance P ([³H]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 µmol/l. Ezlopitant also inhibited SP-induced contraction of guinea pig trachea with a pA₂ 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 [Sar⁹,Met(O₂)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.