Mechanism of action of a new antialdosterone compound, prorenone

Two new aldosterone antagonists, K-prorenoate [potassium 3(17 beta-hydroxy-6 beta, 7 beta-methylen-3-oxo-4-androsten-17 alpha-yl)propionate] and prorenone [3(17 beta-hydroxy-6 beta, 7 beta-methylen-3-oxo-4-androsten-17 alpha-yl) propionic acid gamma-lactone], its lactonic form, were studied in rat kidney using in vitro systems. Study of [3H]prorenone binding by a recently developed computer method indicated a high affinity, low capacity class of sites which are, seemingly, mineralocorticoid receptors. In competition experiments performed on [3H]aldosterone- and [3H]dexamethasone-binding sites, prorenone appeared to be a good competitor for mineralocorticoid-binding sites and a poor competitor for glucocorticoid-binding sites. The specificity of this molecule was further confirmed by its poor ability to displace [3H]dihydrotestosterone from rat prostate androgenic receptors compared to spironolactone [3-(3-oxo-7 alpha-acetylthio-17 beta-hydroxy-4-androsten-17 alpha-yl) propionic acid gamma-lactone]. In the same experiments, K-prorenoate demonstrated a very low affinity for the two types of receptors. The behavior of [3H]prorenone cytosolic complex was also studied in kidney mince experiments, which showed that the [3H]prorenone complex was not able to translocate into the nucleus. Prorenone inhibited the binding of [3H]aldosterone to the receptor and, consequently, the nuclear binding of aldosterone was not observed.