BIOLOGICAL PROFILES OF HIGHLY POTENT NOVEL ENDOTHELIN ANTAGONISTS SELECTIVE FOR THE ETA RECEPTOR

We describe novel potent endothelin (ET) antagonists that are highly potent and selective for the ET(A) receptor (selective to ET-1). Of the synthetic analogs based on ET(A) antagonist BE-18257 A isolated from Streptomyces miskiensis (IC50 value for ET(A) receptor on porcine aortic smooth muscle cells (VSMCs); 1.4-mu-M), the compounds BQ-123 and BQ-153 greatly improved the binding affinity of [I-125]ET-1 for ET(A) receptors on VSMCs (IC50; 7.3 and 8.6 nM, respectively), whereas they barely inhibited [I-125]ET-1 binding to ET(B) receptors (nonselective with respect to isopeptides of ET family) in the cerebellar membranes (IC50; 18 and 54-mu-M, respectively). Associated with the increased affinity for ET(A) receptors, these peptides antagonized ET-1-induced constriction of isolated porcine coronary artery. However, there was a small amount of ET-1-induced vasoconstriction resistant to these antagonists, which paralleled the incomplete inhibition of [I-125]ET-1 binding in the membrane of the aortic smooth muscle layer. These data suggest that the artery has both ET(A) and ET(B) receptors responsible for ET-1-induced vasoconstriction. The antagonists shifted the concentration-response curve to the right for ET-1 in the coronary artery, and increased the apparent dissociation constant in the Scatchard analysis of [I-125]ET-1 binding on the VSMCs without affecting the binding capacity, indicative of the competitive antagonism for ET(A) receptor. In conscious rats, pretreatment with the antagonists markedly antagonized ET-1-induced sustained pressor responses in dose-dependent fashion without affecting ET-1-induced transient depressor action, suggesting that the pressor action is mediated by ET(A) receptors, while the depressor action is mediated by ET(B) receptors. In addition, pretreatment with the potent antagonists prevented ET-1-induced sudden death in mice. Thus, these potent ET(A) antagonists should provide a powerful tool for exploring the therapeutic uses of ET(A) antagonists in putative ET-1-related disorders.