Elsevier

Biochemical Pharmacology

Volume 29, Issue 3, 1 February 1980, Pages 353-357
Biochemical Pharmacology

Importance of the lactonic ring in the activity of steroidal antialdosterones

https://doi.org/10.1016/0006-2952(80)90513-4Get rights and content

Abstract

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, 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.

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    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.

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