Importance of the lactonic ring in the activity of steroidal antialdosterones

The in vivo pharmacological activity of several spirolactone compounds was tested in rats and compared to their ability to compete for [ 3H] aldosterone renal binding sites. Spironolactone, ∗ ∗ Spironolactone: 3-(-3-oxo-7α-acetylthio-17β-hydroxy-4-androsten-17 α-yl) proprionic acid γ-lactone; Canrenone: 3-(17β-hydroxy-6,7-dehydro-3-oxo-4-androsten-17αyl) proprionic acid γ-lactone; Dihydrocanrenone: 3 (17βhydroxy-6β, 7β dihydro-3-oxo-4-androsen-17-α-yl) proprionic acid γ-lactone; K-canrenoate: potassium 3-(17βhydroxy —6,7-dehydro-3-oxo-4-androsten-17α-yl) proprionate. canrenone, dihydrocanrenone and K-canrenoate were all active in vivo, but 17- O-methyl 5,6-dihydro-canrenoic acid, a derivative which cannot be lactonized, was inactive at doses up to 20 mg/kg. Competition experiments were performed on cytosolic renal aldosterone sites labelled with 5 × 10 −9 M [ 3H] aldosterone. Spironolactone, canrenone and dihydrocanrenone were almost equally potent, whereas K-canrenoate and its derivatives exhibited practically no affinity for aldosterone sites. These results strongly suggest that K-canrenoate is only active in vivo when converted into canrenone, a steroid possessing a γ-lactone ring.