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Endothelin@25 – new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12



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Since the discovery of endothelin-1 in 1988, the main components of the signalling pathway have become established comprising three structurally similar endogenous twenty-one amino acids peptides, ET-1, ET-2 and ET-3, that activate two G-protein coupled receptors, ETA and ETB.. Our aim in this review is to highlight the recent progress in endothelin research. The endothelin-like domain peptide, corresponding to prepro-ET-193-166, has been proposed to be co-synthesised and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of endothelin converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for endothelin research.



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British Journal of Pharmacology

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Wiley on behalf of the British Pharmacological Society
Wellcome Trust (096822/Z/11/Z)
BRITISH HEART FDN (PG/05/127/19872)
We thank the British Heart Foundation (PS/02/001, PG/05/127/19872, FS/12/64/130001) Wellcome Trust Programme in Metabolic and Cardiovascular Disease 096822/Z/11/Z, NIHR Cambridge Biomedical Research Centre and the Pulmonary Hypertension Association UK.