The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK₁) receptor. T-2328 inhibited the specific binding of [³H][Sar⁹,Met(O₂)¹¹]substance P to tachykinin NK₁ receptors in human lymphoblastic IM9 cells with K_i of 0.08 nM. In the same assay, K_i for aprepitant, a brain-penetrating NK₁ antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK₁ receptors since the affinities for human NK₂, NK₃ receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK₁ receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK₁ 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 NK₁ antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapy-induced emesis.