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  • br Introduction Our understanding of


    Introduction Our understanding of how ligands interact with G protein coupled receptors is evolving, particularly the recognition that some have the ability to preferentially activate a subset of intracellular signalling cascades – so called pathway biased ligands [1]. Additionally, it is now accepted that recruitment of β-arrestin that occurs following activation of the majority of GPCRs not only results in receptor desensitisation and subsequent internalisation but may also contribute to cellular responses involved in normal physiology and disease such as cell Benzethonium Chloride and proliferation [2]. Therefore, 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]. Whereas bias has been considered a property of synthetic ligands it has recently been reported that for example endogenous opioids also show bias at the μ-opioid receptor [4] indicating that the presence of multiple ligands for a receptor, rather than simply representing physiological redundancy, may allow for nuanced cell specific signalling. Distinct roles for the three endogenous endothelin (ET) peptides are emerging in development and in, for example, ovarian physiology but whether pathway bias may contribute to the physiology and pathophysiology of the endogenous peptides in the ET system has not been explored. 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.
    ET receptors and probe dependence Some of the pharmacology of the endothelin receptors has over the last 20years been described as atypical; not conforming to the basic tenets of receptor pharmacology. Particularly, this has been in differences in the behaviour of the endogenous peptides and synthetic agonists with respect to reversal by washout or blockade/reversal of responses by antagonists in in vitro studies [5], [6]. It is now apparent that for a particular receptor multiple active conformations, rather than just one, are possible and ligands can stabilize different conformations of a receptor that may activate subsets of available down-stream pathways. Therefore, some of the atypical pharmacology reported for ET receptors may be consistent with these agonists showing a degree of functional selectivity, although differences in ligand-receptor kinetics may also contribute to these observations. Additionally, because of the allosteric nature of the interaction of ligand–GPCR–intracellular protein (e.g. G protein) affinity measured in binding assays may differ from affinity measured in functional assays, specifically if different agonists stabilize particular receptor conformations then this allows the potential for orthosteric antagonists to demonstrate agonist specific functional affinities – consistent with previously reported atypical pharmacology of probe dependence [7].