title: Subtype selectivity of a novel endothelin antagonist, FR139317, for the two endothelin receptors in transfected Chinese hamster ovary cells.
abstract: We investigated the receptor-binding properties and the antagonist activities of FR139317, a novel endothelin (ET) antagonist, in transfected Chinese hamster ovary cells permanently expressing the two ET receptor subtypes (ETA and ETB). In displacement analysis using membrane preparations derived from the receptor-expressing cells, FR139317 showed a high affinity for ETA (Ki = 1 nM) and a lower affinity for ETB (Ki = 7.3 microM). FR139317 inhibited ETA-mediated phosphatidylinositol hydrolysis and arachidonic acid release and produced a parallel shift in the dose-response curve for ET-1, with respective pA2 values of 8.2 and 7.7. In contrast, FR139317 had no inhibitory effects on these ET-1-induced responses in ETB-expressing cells. FR139317 itself showed no stimulatory effects on phosphatidylinositol hydrolysis and arachidonic acid release in ETA- and ETB-expressing cells. Thus, FR139317 is a potent, competitive, and highly selective antagonist for ETA. This compound should be a powerful tool for investigation of the physiological properties of ETA and exploration of its role in diseases.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Aramori
authors.forename: H
authors.initials: H
authors.lastname: Nirei
authors.forename: M
authors.initials: M
authors.lastname: Shoubo
authors.forename: K
authors.initials: K
authors.lastname: Sogabe
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Kojo
authors.forename: Y
authors.initials: Y
authors.lastname: Notsu
authors.forename: T
authors.initials: T
authors.lastname: Ono
authors.forename: S
authors.initials: S
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors; D006868:Hydrolysis; D007211:Indoles / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D017466:Receptors, Endothelin / Q000145:classification; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014162:Transfection
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D010716:Phosphatidylinositols; D017466:Receptors, Endothelin; D011994:Recombinant Proteins; C079574:FR 139317; D016718:Arachidonic Acid