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  • br Concluding remarks Some of the clinical trials

    2019-10-09


    Concluding remarks Some of the clinical trials of putative neutral competitive ERAs have been less successful than anticipated 6, 8, 11. This might be because of underestimation of the complexity of the molecular pharmacology of ETA. To resolve this, it will be necessary to define the signaling mechanisms during the long-lasting effects resulting from ETA stimulation. G-protein-independent arrestin-mediated signaling is worth considering 69, 70. In the meantime, it might be informative to combine models elaborated for GPCRs that are acted on by small agonists (e.g. two-state, cubic ternary complex, allosteric ternary complex and allosteric ternary two-state models 32, 33, 39, 40, 42, 43) with models elaborated for GPCRs that are acted on by high-molecular-weight Carmustine (e.g. two-domain model 35, 36, 38). Testing of reversing or curative effects of putative antagonists should take into consideration that ET1 dissociates only slowly from ETA. Renewed interest in structure–activity relationships of endothelins and their receptors might focus on (i) potentially distinct address and message domains and (ii) both affinity and efficacy, including those for recruitment of arrestin. It is also worth considering currently available and future ERAs and physiological antagonists of ETA as negative allosteric modulators. The criteria of allosterism that should be addressed 39, 40, 42 include at least distinct effects on agonist affinity and efficacy, saturability and the probe (or agonist) dependence of these effects. Although challenging, these approaches could result (at least in theory) in drugs that become more effective the more the endogenous ET system is activated and in drugs that can discriminate between the ETA-mediated effects of the distinct endogenous endothelins ET1, ET2 and ET3 39, 40, 42. Because a prominent feature of ETA pharmacology is tight binding of endogenous agonists, particular attention to the rate of dissociation and to the residence time of the agonist on the receptor is required. Several excellent reviews have recently examined various techniques that can be used to study aspects of drug–target binding 71, 72. The reported roles of ETA in a broad variety of diseases 6, 7, 8, 9 and our recent finding that endogenously released CGRP and CGRP receptor activation Carmustine can act as endogenous indirect negative allosteric modulators of ETA function 4, 16, 61 should provide motivation to investigate these issues.
    Acknowledgements
    Introduction Although cisplatin is a highly effective anti-neoplastic agent, its nephrotoxicity is a major clinical problem (Saleh and El-Demerdash, 2005). Cisplatin causes tubular injury through multiple mechanisms, including hypoxia, the generation of free radicals, inflammation, and apoptosis. Additionally, significant interactions among these various pathways may occur in cisplatin injury (Yao et al., 2007). Endothelins have a key role in vascular homeostasis. Three isoforms of endothelin have been identified: the originally described endothelin-1 (ET-1) and two similar peptides, ET-2 and ET-3. Two endothelin receptor subtypes, termed ETA and ETB, have been cloned and sequenced. ETA receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction. ETB receptors have approximately equal affinities for ET-1 and ET-3 and are located on vascular endothelial cells, where they mediate release of prostaglandins-I2 (PGI2) and nitric oxide (NO) (Takaoka et al., 2000). Both receptor subtypes belong to the G protein-coupled seven-transmembrane domain family of receptors. Endothelins cause dose-dependent vasoconstriction in most vascular beds. There is increasing evidence that endothelins participate in a variety of cardiovascular diseases (Takaoka et al., 2000), including hypertension, cardiac hypertrophy, as well as in renal failure (Kone, 2004). They act on the kidneys to cause vasoconstriction and decrease glomerular filtration rate and sodium and water excretion (Takaoka et al., 2000).