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Watanabe Y, Asai H, Ishii T, Kiuchi S, Okamoto M, Taniguchi H, Nagasaki M, Saito A: Pharmacological characterization of T-2328, 2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl] amino] methyl]-[1, 1'-biphenyl]-4-carbonitrile dihydrochloride, as a brain-penetrating antagonist of tachykinin NK1 receptor. J Pharmacol Sci. 2008 Jan;106(1):121-7. Epub 2008 Jan 11.
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. |
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