title: Pharmacological profile of FR139317, a novel, potent endothelin ETA receptor antagonist.
abstract: The effects of FR139317 on the cardiovascular system were investigated in cultured cells, isolated organs and whole animals. FR139317 inhibited the specific binding of [125]endothelin(ET)-1 to porcine aortic microsomes in a concentration-dependent, monophasic fashion with an IC50 of 0.53 nM. In contrast, FR139317 showed low affinity for [125I]ET-1 specific binding sites in porcine kidney (IC50, 4.7 microM). In isolated rabbit aorta, FR139317 shifted the ET-1-induced concentration-contractile response curve to the right with a pA2 value of 7.2 and lacked agonist activity. A single (i.v.) bolus dose of FR139317 completely inhibited the pressor response to ET-1 in vivo, but had no effect on the initial depressor response in conscious normotensive rats. These data indicate that FR139317 is a potent, highly specific ETA receptor antagonist. In addition, FR139317 also inhibited ET-1 induced [3H]thymidine incorporation in cultured vascular smooth muscle cells from rat aorta (IC50, 4.1 nM), suggesting that ET-1-induced mitogenesis is mediated only by the ETA receptor. FR139317 could become a useful tool for investigating the physiological and pharmacological actions of ET.
authors.affiliation: Exploratory Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sogabe
authors.forename: H
authors.initials: H
authors.lastname: Nirei
authors.forename: M
authors.initials: M
authors.lastname: Shoubo
authors.forename: A
authors.initials: A
authors.lastname: Nomoto
authors.forename: S
authors.initials: S
authors.lastname: Ao
authors.forename: Y
authors.initials: Y
authors.lastname: Notsu
authors.forename: T
authors.initials: T
authors.lastname: Ono
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; C079574:FR 139317; D004247:DNA