Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor

doi:10.1016/0024-3205(92)90331-I

Life Sciences

Volume 50, Issue 4, 1992, Pages 247-255

https://doi.org/10.1016/0024-3205(92)90331-I Get rights and content

Abstract

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-18257A isolated from Streptomyces misakiensis (IC₅₀ value for ET_A receptor on porcine aortic smooth muscle cells (VSMCs); 1.4μM), the compounds BQ-123 and BQ-153 greatly improved the binding affinity of [¹²⁵I]ET-1 for ET_A receptors on VSMCs (IC₅₀; 7.3 and 8.6 nM, respectively), whereas they barely inhibited [¹²⁵I]ET-1 binding to ET_B receptors (nonselective with respect to isopeptides of ET family) in the cerebellar membranes (IC₅₀; 18 and 54 μM, 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 [¹²⁵I]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 [¹²⁵I]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.

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Citation Excerpt :
Endothelin acts through two pharmacologically distinct G-protein–coupled receptors: endothelin A receptor (ETA) and endothelin B receptor (ETB). ETA primarily exerts vasoconstrictor and proliferative effects of ETs,23 whereas ETB induces endothelial-dependent vasodilatation through nitric oxide and prostaglandin production.24,25 Also, ETB regulates sodium and water handling in the kidney.26
The impact of endothelin antagonism for the management of hypertension is a topic explored in multiple preclinical and clinical studies. Endothelin-receptor antagonists are an effective therapy for primary and resistant hypertension, but they are not widely used. This is owing to side effects shown in large clinical trials as well as the availability of many alternative agents to manage blood pressure effectively. However, the study of endothelin and its close ties to hypertension is evolving. Recent preclinical studies have explored new applications of more selective endothelin-receptor antagonists. The studies suggested that patients with certain subtypes of hypertension may benefit more from endothelin-receptor blockade than simply patients with primary hypertension. We review this and other data on this topic.

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Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor

Abstract

Nature

Biochem. Biophys. Res. Commun.

Jap. J. Pharmacol.

Nature

Nature

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

J. Cardiovasc. Pharmacol.

Biochem. Biophys. Res. Commun.

The Endothelins

J. Antibiotics

J. Antibiotics

Biological profiles of highly potent novel endothelin antagonists selective for the ET_A receptor