Mechanism of Action of the Potent Sodium-Retaining Steroid 11,19-Oxidoprogesterone

Abstract

We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodiumretaining compounds tested in those studies was 11,19-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19-oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19-oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone.In contrast to glucocorticoids, which exhibit a slightly torsioned steroid nucleus at the A/B-ring junction, mineralocorticoids seem to require a flat conformation for optimal activity (Duax et al., 1978;Lantos et al., 1981;Yamakawa et al., 1986;Burton et al., 1995). Consistent with this structural requirement, we have reported previously (Burton et al., 1995) that the highly planar synthetic steroid 11,19-oxidoprogesterone (11-OP; see structure in Fig. 1) exhibits potent sodium-retaining activity. In this sense, 11-OP is equivalent to the biological activity measured with 21-deoxycorticosterone (DOC) and, at some doses, even approaches the effects of aldosterone (ALDO). On the other hand, 11-OP differs from endogenous mineralocorticoids in its relatively lower affinity for mineralocorticoid receptor (MR), which is ϳ50 nM as compared with 4 nM for ALDO and 10 nM for DOC.In contrast to the natural mineralocorticoids ALDO and DOC, the synthetic steroid 11-OP lacks a C 21 -hydroxyl group. Also, 11-OP does not possess a functional C 18 -methyl group as found on ALDO and the strong synthetic mineralocorticoid 18-vinylprogesterone. Nevertheless, the overall flat 11-OP is a strong sodium-retaining steroid. In contrast, its highly bent isomer 6,19-oxidoprogesterone (6-OP) exhibits negligible, if any, mineralocorticoid activity. These interesting features suggest that a ...

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