The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK(1)) receptor. T-2328 inhibited the specific binding of [(3)H][Sar(9),Met(O(2))(11)]substance P to tachykinin NK(1) receptors in human lymphoblastic IM9 cells with K(i) of 0.08 nM. In the same assay, K(i) for aprepitant, a brain-penetrating NK(1) antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK(1) receptors since the affinities for human NK(2), NK(3) receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK(1) receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK(1) receptor. T-2328 (0.03-0.1 mg/kg, i.v.) and aprepitant (1 - 3 mg/kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1-0.3 mg/kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg/kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK(1) antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapy-induced emesis.