Pharmacological characterization of a potent nonpeptide endothelin receptor antagonist, 97-139

S Mihara, S Nakajima, S Matumura, T Kohnoike and M Fujimoto

Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.

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)

Volume 268, Issue 3, pp. 1122-1128, 03/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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