The
anti-emetic effects of a novel
tachykinin NK(1) receptor antagonist,
ezlopitant ((2S,3S-cis)-2-diphenylmethyl)- N-[(2-methoxy, 5-isopropylphenyl)methyl]-1-azabicyclo- [2.2.2]octan-3-
amine), were investigated in ferrets.
Ezlopitant inhibited [(3)H]
substance P ([(3)H]SP) binding to the human, guinea pig, ferret and gerbil
NK(1) receptors (K(i) = 0.2, 0.9. 0.6 and 0.5 nmol/l, respectively), but had no affinity to
NK(2) and
NK(3) receptors up to 1 micromol/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
NK(1) receptors in the brain. These findings indicate that
ezlopitant is a potent and selective
NK(1) receptor antagonist, and that it inhibits both acute and delayed
emetic reactions induced by
cisplatin in ferrets via acting on
NK(1) receptors in the central nervous system.