Structure-activity relationship of new steroidal aldosterone antagonists. Comparison of the affinity for mineralocorticoid receptors in vitro and the antialdosterone activity in vivo.

The ability of 18 steroids with structures similar to spironolactone, progesterone or aldosterone to compete with [3H]aldosterone for binding at rat renal cytosol receptors in vitro and the antialdosterone activity in vivo were tested in comparison with spironolactone. The affinity of these compounds for mineralocorticoid receptors was then compared with their pharmacological action in rats. Replacement of the 17-spirolactone ring by a 17 alpha-hydroxypropyl group and a 17 beta-hydroxyl group resulted in a loss of affinity for the [3H]aldosterone binding sites but not in a reduction in antialdosterone activity in vivo. Compared to spironolactone, C6/C7 unsaturated compounds showed a reduced activity both in vitro and in vivo. Substitution of the 7 alpha-thioacetyl group of spironolactone by a 6,7-methylene group in the beta position (prorenone) increased the affinity to the receptor as well as the biological activity by 52 and 41%, respectively. Introduction of a methyl-group at the D-ring of spironolactone resulted in similar significant drops in activity both in vitro and in vivo. The progesterone like steroids were weak competitors for aldosterone in vitro and in vivo. Two of three aldosterone like steroids (18-deoxyaldosterones) still exhibit mineralocorticoid activity and one analogue could be classified as a weak aldosterone antagonist. The studies show in general that the comparison of the affinity for mineralocorticoid receptor sites with the antimineralocorticoid activity in vivo is a valuable procedure in the search for new antimineralocorticoid substances.