ETA-receptor antagonists or allosteric modulators?

Autor: De Mey JG; Department of Pharmacology, Maastricht University, Maastricht, The Netherlands. j.demey@maastrichtuniversity.nl, Compeer MG, Lemkens P, Meens MJ
Jazyk: angličtina
Zdroj: Trends in pharmacological sciences [Trends Pharmacol Sci] 2011 Jun; Vol. 32 (6), pp. 345-51. Date of Electronic Publication: 2011 Apr 12.
DOI: 10.1016/j.tips.2011.02.018
Abstrakt: The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET(A) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds that discriminate between ET(A)-mediated effects of the endogenous isopeptides ET1, ET2 and ET3 and that become more effective when the activity of the endogenous endothelin system is elevated.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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