Potency of PD155080, an Orally Active ETA Receptor Antagonist, Determined for Human Endothelin Receptors

Abstract

We have determined, for the first time, the potency of a new ETA-selective endothelin (ET) antagonist, PD155080, for human endothelin receptors. In sections of human left ventricle (n = 3) and human kidney (n = 5) PD155080 competed for specific [125I]ET-1 binding with Kd values at the ETA receptor of 221.4 +/- 25 nM and 19.0 +/- 23 nM and at the ETB receptor of 86.5 +/- 9.0 microM and 17.7 +/- 1.4 microM. PD155080 therefore has up to 1,000-fold selectivity for the human ETA receptor. The ability of this compound to antagonize ET-1-mediated vasoconstriction was determined in human isolated coronary artery, saphenous vein, and left internal mammary artery. Increasing concentrations of PD155080 caused a progressive, parallel rightward shift of the ET-1 concentration-response curve without detrimental effect on the maximal response to ET-1. The pA2 values determined by Schild analysis were 6.87 in coronary artery (n = 5), 6.75 in saphenous vein (n = 7), and 7.25 in mammary artery (n = 6). Slopes of the Schild regression lines were not significantly different from one, indicating a competitive mode of action. In addition, PD155080 (1 microM) fully reversed the established contraction to ET-1 (30 nM) in saphenous vein. The potency of this compound is comparable to that reported for the ETA-selective peptide antagonist BQ123 [cyclo(D-Trp-L-Asp-L-Pro-D-Val-L-Leu)], which is effective in limiting tissue damage caused by ET-1 in animal models of pathologic vasospasm. PD155080 may therefore be a good candidate for clinical use in diseases, such as subarachnoid hemorrhage, in which the ET system is implicated.