The renal action of spirorenone and other 6 beta,7 beta; 15 beta,16 beta-dimethylene-17-spirolactones, a new type of steroidal aldosterone antagonists.
The aldosterone antagonistic activity in vivo and the affinity for mineralocorticoid receptors (MCR) in vitro of 3-(17 beta-hydroxy-6 beta,7 beta; 15 beta,16 beta-dimethylene-3-oxo-1, 4-androstadiene-17 alpha-yl) propionic acid gamma-lactone (spirorenone), a new aldosterone antagonist, and four of its derivatives were studied in comparison with spironolactone in rats. Spirorenone was 8.6 times as potent as spironolactone, but showed a lower affinity for the MCR than the standard. The C1/C2 saturated derivative (compound I) had 7.6 times the antialdosterone potency and 2 times the binding activity of spironolactone. The 17-spiroether derivative of spirorenone (compound II) showed a lower aldosterone antagonistic activity (1.7 the potency of spironolactone) as well as a lower affinity for the MCR (0.5 the affinity of spironolactone). The analogue with a 17 beta-hydroxyl group and a 17 alpha-hydroxypropyl side chain (compound III) possessed a very low binding capacity for MCR (1/10 of that of spironolactone) but still a 1.3 times higher antialdosterone activity than spironolactone. This result is probably due to a transformation of compound III to an active metabolite in vivo. Finally, the derivative with a reversed configuration of the 17-spirolactone ring (compound IV) had no biological activity in vivo and no affinity for the MCR. These results show that spirorenone or one of its active derivatives might lead to a new series of potent aldosterone antagonists.
D000315:Adrenalectomy; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000730:Androstadienes; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D013148:Spironolactone; C035143:spirorenone