Mineralocorticoid receptor interactions

There are essential structural features that are necessary for glucocorticoid activity. The natural glucocorticoids also interact with the mineralocorticoid receptor and, therefore, will have salt-retaining properties. A large number of synthetic analogues have been prepared to decrease the mineralocorticoid effects in favor of increasing the glucocorticoid (anti-inflammatory) effect of the steroids. In addition, many derivatives are prepared to enhance pharmacokinetic parameters, most notably the synthesis of lipophilic and hydrophilic esters. 

In particular, it should be noted that since 11-deoxycorticosterone does not exhibit glucocorticoid activity yet, it is a powerful mineralocorticoid and has only two potentially reactive substituents capable of reacting with a receptor, and the interaction should occur by way of a Cj-keto and/or a Ci7j3-C0-CH20H groups. The necessity of either a simultaneous presence of acidic functions at Cu and or the necessity of simultaneous absence of acidic functions at and C17 in the structure of the pregnane system is also apparent. 

The slight conformational modification of the A ring (revealed by X-ray diffraction), which probably comes from an interaction between the fluorine on C-9 and the axial OH on C-1, could contribute to the differences of affinity. However, X-ray structure of the cocrystallized form of fluorocortisol with the glucocorticoid receptor does not explain the impact of fluorine on the increase in affinity (cortisol = 0.67 pM versus 9a-fluorocortisol Xj = 0.027 The fluorine at C-9 can reduce the oxidative metabolism of hydroxyl-11. Oxidation of OH-11 into ketone is fast for the cortisol and is accompanied by the loss of biological activity. However, this hypothesis would imply metabolites to contribute to the mineralocorticoid activity. 

Normally, aldosterone exerts its mineralocorticoid actions via interaction with its receptors —>T formation of Na+ channels on the luminal membrane of the principal cell and — T activity of Na+/K+ and II1 exchangers. Na+ diffuses through its channels, increasing intracellular positive charge, which leads to extrusion of K+ into the lumen. By mechanisms that are unclear, Na+ entry into cells of the CT leads to an increase in the energy-dependent extrusion of protons across the luminal membranes of intercalated cells. 

A. Mechanism of Action Corticosteroids enter the cell and bind to cytosolic receptors that transport the steroid into the nucleus. The steroid-receptor complex alters gene expression by binding to glucocorticoid response elements (GREs) or mineralocorticoid-specific elements (Figure 39-2). Tissue-specific responses to steroids are made possible by the presence in each tissue of different protein regulators that control the interaction between the hormone-receptor complex and particular response elements. 

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