title: Binding of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors, to guinea pig lung membranes.
abstract: Arachidonic acid metabolites mediate inflammatory responses at a cellular level. The affinity of the newly synthesized compound YM158, 3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesuf onyl)propyl-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D4 and thromboxane A2 receptors was examined in radioligand binding assays. YM158 inhibited [3H]leukotriene D4 and [3H]U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha) binding to guinea pig lung membrane preparations, with Ki values of 0.64+/-0.06 nM for leukotriene D4 and 5.0+/-0.88 nM for thromboxane A2 receptors. The Hill coefficients (nH) did not significantly differ from unity, indicating that this antagonism is competitive. In contrast, YM158 showed no affinity for several other receptors, including neurotransmitter-related (alpha1-, alpha2-, beta-adrenoceptors, histamine, 5-HT, muscarinic, sigma), C5a, opioid, Ca2+ channel, K+ channel, protein kinase C, bradykinin, endothelin, neurokinin and platelet activating factor receptors. These studies indicate that YM158 is a highly selective dual antagonist for leukotriene D4 and thromboxane A2 receptors, and this has potential clinical and research applications.
authors.affiliation: Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical, Ibaraki, Japan. arakida.yasuhito@yamanouchi.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Arakida
authors.forename: K
authors.initials: K
authors.lastname: Ohga
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Yokota
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: T
authors.initials: T
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Honda
mesh_terms: D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D006168:Guinea Pigs; D020024:Leukotriene Antagonists / Q000378:metabolism* / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D011869:Radioligand Assay; D018077:Receptors, Leukotriene / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism* / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D017482:Receptors, Thromboxane; D013777:Tetrazoles; D013844:Thiazoles; C115704:YM 158; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor