PHARMACOLOGICAL CHARACTERIZATION OF A POTENT NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST, 97-139

The endothelin (ET) receptor antagonist activity of 97-139 {27-O-3-[2- (3-carboxy-acryloylamino)- 5-hydroxyphenyl]-acryloyloxy myricerone, so dium salt} was studied. In rat aortic smooth muscle A7r5 cells that ex press ET(A) receptors and human Girardi heart cells that express ET(B) receptors, 97-139 displaced specifically bound [I-125]ET-1 with the K -i values of 1.0 +/- 0.2 and 1000 +/- 200 nM, respectively. The compou nd caused a concentration-dependent inhibition of ET-1-induced increas es in intracellular Ca++ levels in A7r5 cells, but not in Girardi hear t cells. 97-139 also inhibited ET-1-induced [H-3]thymidine incorporati on in A7r5 cells (IC50 = 0.92 +/- 0.48 nM). In rat aortic rings, 97-13 9 produced parallel rightward shifts in the ET-1 concentration-respons e curve without affecting the maximal contractile response (pA(2) = 8. 8 +/- 0.4). Administration of 97-139 (0.03-1.0 mg/kg) i.v. to pithed r ats resulted in dose-dependent inhibition of the presser response to E T-1. The in vivo potency of 97-139 was almost the same as that of BQ-1 23, although the potencies of 97-139 in binding assays and in vitro fu nctional 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. Although 97- 139 is not as potent in in vivo assay as expected from the data in bin ding assays and in vitro functional assays, the nonpeptidic structure makes 97-139 a valuable new tool for investigating the physiological a nd pharmacological actions of ET.