Clinical and experimental pharmacology & physiology
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Clin. Exp. Pharmacol. Physiol. · Oct 2004
Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor.
The importance of mineralocorticoid receptor (MR) antagonists in the treatment of cardiovascular disease has been emphasised by two recent clinical trials, one using spironolactone and the other using a new selective MR antagonist, namely eplerenone. Eplerenone has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of eplerenone to the MR were investigated using chimeras created between the ligand-binding domains (LBD) of the MR and the GR. ⋯ Similar results were obtained using another MR antagonist, namely spironolactone. Modelling of eplerenone binding to the MR LBD, based on the GR LBD crystal structure, suggests that amino acids 820-844 affect the overall shape of the ligand-binding pocket and that eplerenone acts as an MR antagonist because it fails to stabilize the active conformation of the receptor. In contrast with results with the MR antagonists eplerenone and spironolactone, amino acids 820-844 are sufficient in themselves to confer high-affinity aldosterone binding to the MR, suggesting that the binding determinants of the two antagonists are similar to each other but differ from those of aldosterone.