title: Pharmacological characterization of a potent nonpeptide endothelin receptor antagonist, 97-139.
abstract: The endothelin (ET) receptor antagonist activity of 97-139 [27-O-3-[2-(3-carboxy-acryloylamino)-5-hydroxyphenyl]-acryloylo xy myricerone, sodium salt] was studied. In rat aortic smooth muscle A7r5 cells that express ETA receptors and human Girardi heart cells that express ETB receptors, 97-139 displaced specifically bound [125I]ET-1 with the Ki values of 1.0 +/- 0.2 and 1000 +/- 200 nM, respectively. The compound caused a concentration-dependent inhibition of ET-1-induced increases in intracellular Ca++ levels in A7r5 cells, but not in Girardi heart cells. 97-139 also inhibited ET-1-induced [3H]thymidine incorporation in A7r5 cells (IC50 = 0.92 +/- 0.48 nM). In rat aortic rings, 97-139 produced parallel rightward shifts in the ET-1 concentration-response curve without affecting the maximal contractile response (pA2 = 8.8 +/- 0.4). Administration of 97-139 (0.03-1.0 mg/kg) i.v. to pithed rats resulted in dose-dependent inhibition of the pressor response to ET-1. The in vivo potency of 97-139 was almost the same as that of BQ-123, although the potencies of 97-139 in binding assays and in vitro functional assays were about one order of magnitude higher than those of BQ-123. This discrepancy might involve high binding toward albumin in plasma because 95% plasma and 4% albumin reduced the apparent binding affinity of 97-139 by 22- to 24-fold, but not of BQ-123.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mihara
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Matumura
authors.forename: T
authors.initials: T
authors.lastname: Kohnoike
authors.forename: M
authors.initials: M
authors.lastname: Fujimoto
mesh_terms: D000418:Albumins / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001769:Blood; D002109:Caffeic Acids / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D003655:Decerebrate State; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009828:Oleanolic Acid / Q000031:analogs & derivatives*; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000418:Albumins; D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C086421:S 0139; C075745:myriceron caffeoyl ester; D009828:Oleanolic Acid; D004247:DNA; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium