title: WS9326A, a novel tachykinin antagonist isolated from Streptomyces violaceusniger no. 9326. II. Biological and pharmacological properties of WS9326A and tetrahydro-WS9326A (FK224)
abstract: WS9326A binds competitively to [3H]substance P (NK-1 receptor) binding sites on guinea-pig lung membranes (IC50 = 3.6 x 10(-6) M), and acts as a tachykinin antagonist in various functional assays. WS9326A inhibited tracheal constrictions produced by exogenously added substance P and neurokinin A, with IC50 values of 9.7 x 10(-6) M and 3.5 x 10(-6) M, respectively. WS9326A inhibited neurokinin A-induced bronchoconstriction in a dose dependent manner when administered to guinea-pigs intravenously together with neurokinin A, and was also effective in preventing capsaicin-induced bronchoconstriction, which is known to be caused by release of endogenous tachykinins (substance P and neurokinin A). FK224 (tetrahydro-WS9326A; catalytic hydrogenation of WS9326A gave FK224) was more potent than WS9326A in the [3H]substance P receptor binding assay using guinea-pig lung membrane (IC50 = 1.0 x 10(-7) M).
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Murai
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: S
authors.initials: S
authors.lastname: Kiyoto
authors.forename: M
authors.initials: M
authors.lastname: Okuhara
authors.forename: M
authors.initials: M
authors.lastname: Kohsaka
authors.forename: H
authors.initials: H
authors.lastname: Imanaka
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013302:Streptomyces / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects; D047630:Depsipeptides
chemical_list: D007783:Lactones; D010456:Peptides, Cyclic; D013373:Substance P; D015320:Tachykinins; C076469:WS 9326A; D047630:Depsipeptides; C075570:FK 224