THE MINERALOCORTICOID ACTIVITY OF PROGESTERONE DERIVATIVES DEPENDS ON THE NATURE OF THE C-18 SUBSTITUENT

To investigate the role of the C-18 substituents in the agonist/antagonist properties of mineralocorticoids, the activities of certain C-18-substituted progesterone (P) derivatives were examined. These compounds were characterized by an unsaturated side-chain in the case of 18-vinylprogesterone (18VP) and 18-ethynylprogesterone (18EP) and by an enone group in the case of 18-oxo-18-vinylprogesterone (18OVP). P and its 18-substituted derivatives bind to the recombinant human MR (hMR) overexpressed in Sf9 cells with the following hierarchy of affinity: P > aldosterone > 18VP > 18EP >> 18OVP. Functional cotransfection assays in CV-1 cells, using mouse mammary tumor virus promoter as a steroid receptor-inducible DNA target sequence, indicated that the mineralocorticoid activity depends on the nature of the C-18 substituent. 18VP and 18EP retained the antimineralocorticoid feature of P, with the following order of activity: P = 18VP > 18EP. The antagonist potency of 18VP was higher (IC50, similar to 10(-8) M) than that of spironolactone (IC50, similar to 7 X 10(-8) M), the most widely used aldosterone antagonist. Interestingly, introducing an oxo function at C-18 conferred agonist mineralocorticoid properties; 18OVP behaves as a full agonist (E(50), similar to 10(-7) M) with no antagonist activity. In contrast to what was observed when the three 18-substituted P derivatives acted through hMR, they retained the agonist feature of P through the human P receptor, with the following order of potency: P > 18VP = 18OVP 18EP. The activity of the 18-substituted P derivatives through the human glucocorticoid receptor was only detected at concentrations higher than 10(-6) M; P and 18VP displayed a partial antagonist activity, whereas 18OVP had a full agonist activity (ED(50), similar to 2: x 10(-6) M). Thus, the presence of an oxo group at C-18(18OVP) does not change the agonist feature of P through human P receptor, but confers to the ligand an agonist activity through hMR, suggesting that the C-18 carbonyl group of aldosterone plays a crucial role in its agonist activity.