Abstract
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 ETA signalling in ovarian cancer has been delineated in some detail and this has led to the suggestion that the development of ETA G protein biased agonists or β-arrestin biased antagonists should be explored.
Highlights
Our understanding of how ligands interact with G protein coupled receptors is evolving, the recognition that some have the ability to preferentially activate a subset of intracellular signalling cascades – so called pathway biased ligands [1]
It is accepted that recruitment of β-arrestin that occurs following activation of the majority of GPCRs results in receptor desensitisation and subsequent internalisation but may contribute to cellular responses involved in normal physiology and disease such as cell migration and proliferation [2]
Exploiting ligand bias is likely to lead to the development of more effective and better tolerated medicines. This has so far been most clearly demonstrated for the μ opioid receptor where the agonist TRV130, a molecule that discriminates between beneficial analgesia and detrimental adverse effects such as respiratory depression and nausea, exhibited an improved therapeutic profile compared to morphine in a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers [3]
Summary
Our understanding of how ligands interact with G protein coupled receptors is evolving, the recognition that some have the ability to preferentially activate a subset of intracellular signalling cascades – so called pathway biased ligands [1]. Exploiting ligand bias is likely to lead to the development of more effective and better tolerated medicines This has so far been most clearly demonstrated for the μ opioid receptor where the agonist TRV130, a molecule that discriminates between beneficial analgesia and detrimental adverse effects such as respiratory depression and nausea, exhibited an improved therapeutic profile compared to morphine in a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers [3]. In contrast the potential for targeting the endothelin receptors with synthetic biased ligands is starting to be considered. This brief review discusses current research on biased signalling at the ET receptors and therapeutic areas of interest
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