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

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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 Ki of 0.08 nM. In the same assay, Ki 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.