title: 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.
abstract: 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.
authors.affiliation: Pharmacology Laboratory, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa, Japan. watanabe.yumi@mf.mt-pharma.co.jp
authors.forename: Yumi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Asai
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Ishii
authors.forename: Satoko
authors.initials: S
authors.lastname: Kiuchi
authors.forename: Masahito
authors.initials: M
authors.lastname: Okamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents; D000077608:Aprepitant; D001665:Binding Sites; D001921:Brain / Q000187:drug effects*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002945:Cisplatin; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D005849:Gerbillinae; D006801:Humans; D007700:Kinetics; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000932:Antiemetics; D000970:Antineoplastic Agents; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C526892:T-2328; C062618:substance P, Sar(9)-Met(O2)(11)-; C068032:GR 73632; D000077608:Aprepitant; D013373:Substance P; D002945:Cisplatin