The effect of
T-2328 {2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-
biphenyl]-4-carbonitrile dihydrochloride}, a novel
tachykinin NK(1)-receptor antagonist, was examined on
cisplatin-induced
emesis in ferrets.
Cisplatin induced acute
emesis in 24 h and delayed
emesis during 24 and 72 h, respectively.
Ondansetron, a 5-HT(3) antagonist, almost completely blocked the acute
emesis and transiently reduced the delayed
emesis. In contrast,
T-2328 elicited long-lasting
anti-emetic effects on both acute and delayed phases by a single
intravenous administration. Suppression of delayed
emesis was not due to elimination of the acute phase because the delayed
emesis was also suppressed by administration after the onset of delayed
emesis. Persistent blockade of
NK(1) receptors in the brain was demonstrated by inhibition of the NK(1) agonist-induced foot tapping response for over 24 h. An appreciable amount of
T-2328 was present in the brain 32 and 72 h after the injection. The NK(1) agonist-induced contractions of isolated ileum in guinea pigs was antagonized with IC(50) values of 1.4 nM in an insurmountable manner. It is likely that
T-2328 exerts the long-lasting
anti-emetic effect by not only long-term presence in the brain but also its insurmountable inhibition of
NK(1) receptors.