What is it about?
The is a review of endothelins, a family of three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. This review is a summary of the current state of knowledge about the pharmacology of endothelin agonists and antagonists, the clinical pharmacology of endothelin ligands in experimental medicine and in the clinic and the effect of knocking-out genes in animal models.
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Why is it important?
Blood vessels in the body control the flow of blood to organs by balancing the actions of chemical messengers that constrict the vessel wall with chemical messengers causing blood vessels to relax, so increasing the flow of blood. Endothelin is the most powerful constrictor of blood vessels yet discovered. Clincal use of ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection
Perspectives
Intriguingly, genes encoding the endothelin peptides are present only among vertebrates. The endothelin signalling pathway is therefore a vertebrate innovation and may reflect the need for a very powerful chemical messenger to constrict vessels for a long period of time to avoid loss of blood. However, in certain diseases levels of the peptide increase causing unwanted constriction for example in pulmonary arterial hypertension and this property become highly detrimental to health.
Dr Anthony P Davenport
University of Cambridge
It was interesting to follow one GPCR through the major chemogenomic resources as part of this review. We could also resolve some of these by time rather that just simple retrieval. As can be seem in Fig 11 the documentation of chemical modulators of all types for ENDRA shows a prnounced rise (around 2000) and fall (from 2010 onward). Analagous changes of drug target popularity have been reported before (PubMed 24204758). Recording a fall in ENDRA-directed small molecule modulation efforts is open to a number of intepretations that are difficult to test. One of these is that, after what could be seen as a burst of success, the further optimisation, in terms of potency and selectivity, became pariticularly difficult. An alternative explaination, from a pharmaceutical company perspective, is that the commercial attractiveness of new ENDRA modulators is lower, since they have to circumvent the patents already filled. Whichever of these influcencess might be the cominant cause of the drop off in new medicinal chemistry and lead compounds it seems likely that an eventual 3D crystal structure would kick off another burst of chemistry optimisation, possibly including allosteric modulators.
Dr Christopher Southan
Read the Original
This page is a summary of: Endothelin, Pharmacological Reviews, March 2016, American Society for Pharmacology & Experimental Therapeutics (ASPET),
DOI: 10.1124/pr.115.011833.
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