Evidence for biased agonists and antagonists at the endothelin receptors

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• 作者：Janet J. Maguire ^{jjm1003@medschl.cam.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：G protein coupled receptors ; Endothelin ; ETA ; ETB ; Biased agonism ; Biased antagonism ; β-Arrestin ; Bosentan ; Pathway selectivity ; IRL1620
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：159
• 期：Complete
• 页码：30-33
• 全文大小：438 K

文摘

Biased ligands represent a new strategy for the development of more effective and better tolerated drugs. To date there has been a paucity of research exploring the potential of ligands that exhibit either G protein or β-arrestin pathway selectivity at the endothelin receptors. Re-analysis of data may allow researchers to determine whether there is existing evidence that the endogenous ET peptides or currently available agonists and antagonists exhibit pathway bias in a particular physiological or disease setting and this is explored in the review. An alternative to molecules that bind at the orthosteric site of the ET receptors are cell penetrating peptides that interact with a segment of an intracellular loop of the receptor to modify signalling behaviour. One such peptide IC2B has been shown to have efficacy in a model of pulmonary arterial hypertension. Finally, understanding the molecular pathways that contribute to disease is critical to determining whether biased ligands will provide clinical benefit. The role of ET_A signalling in ovarian cancer has been delineated in some detail and this has led to the suggestion that the development of ET_A G protein biased agonists or β-arrestin biased antagonists should be explored.