Importance of Subtype Selectivity for Endothelin Receptor Antagonists in the Human Vasculature

Maguire, Janet J.; Davenport, Anthony P.

doi:10.1007/978-0-85729-920-8_10

Cited by 2 publications

(4 citation statements)

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“…Bosentan reportedly has similar affinity for both of the endothelin receptor subtypes (Clozel et al, 1994), ET A and ET B , whereas ambrisentan is an ET A selective compound (Vatter and Seifert, 2006) although the degree of ET A selectivity reported in the literature varied depending on whether it was determined using animal or human, cloned or native receptor systems (Maguire and Davenport, 2012;Palmer, 2009;Vatter et al, 2002). A third antagonist, sitaxentan (Wu et al, 1997), is much more ET A selective than ambrisentan.…”

Section: Introductionmentioning

confidence: 94%

Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

et al. 2012

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Section: Introductionmentioning

confidence: 94%

Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

et al. 2012

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“…Measurement of the affinity (the equilibrium dissociation constant or K D ) of each compound at the two receptor sub-types can be accurately determined using non-linear iterative curve fitting. Comparison of the two affinities provides a measure of the selectivity for each subtype ( Maguire and Davenport, 2012 ).…”

Section: Classification Of Selective Agonists and Antagonistsmentioning

confidence: 99%

“…ET B agonists have been tested for clinical application in cancer ( Maguire and Davenport 2012 ; Gulati et al, 2012 ). A Phase 1 clinical trial of IRL-1620 (SPI-1620, Spectrum Pharmaceuticals; (Henderson, Nevada)) was carried out in patients with recurrent progressive carcinoma and shown to selectively and transiently increase tumor blood flow ( Gulati et al, 2012 ).…”

Section: Classification Of Selective Agonists and Antagonistsmentioning

confidence: 99%

“…It is now recognized that signaling bias is best demonstrated by comparing the relative potencies of agonists to a standard, preferably an endogenous agonist, in assays that interrogate multiple G-protein-dependent and -independent pathways that have relevance to ET physiology or pathophysiology. One study ( Maguire and Davenport, 2012 ) has reported that the endogenous ET peptides show similar rank order of potencies and maximum responses in both a G-protein-dependent constrictor assay and cell-based β -arrestin recruitment assay, whereas sarafotoxin 6b was a full agonist in the constrictor assay but a partial agonist in the β -arrestin assay, suggesting the potential to generate biased ET agonists. It is interesting to speculate that a reduction in the ability of the toxin to trigger receptor desensitization may have been a result of evolutionary selection to prolong the effect on prey of envenomation.…”

Section: Classification Of Selective Agonists and Antagonistsmentioning

confidence: 99%

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Endothelin

et al. 2016

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The endothelins comprise 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. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. 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. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

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Importance of Subtype Selectivity for Endothelin Receptor Antagonists in the Human Vasculature

Cited by 2 publications

References 91 publications

Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

Endothelin

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