PT  - JOURNAL ARTICLE
AU  - M de Gasparo
AU  - U Joss
AU  - H P Ramjoué
AU  - S E Whitebread
AU  - H Haenni
AU  - L Schenkel
AU  - C Kraehenbuehl
AU  - M Biollaz
AU  - J Grob
AU  - J Schmidlin
TI  - Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro.
DP  - 1987 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 650--656
VI  - 240
IP  - 2
4099  - http://jpet.aspetjournals.org/content/240/2/650.short
4100  - http://jpet.aspetjournals.org/content/240/2/650.full
SO  - J Pharmacol Exp Ther1987 Feb 01; 240
AB  - The use of spironolactone, the most commonly used antimineralocorticoid compound, is limited by the occurrence of sexual endocrine effects. New antagonists are therefore required which lack these unwanted effects. Three 9 alpha,11 alpha-epoxy-derivatives of known aldosterone antagonists (spironolactone, prorenone and mexrenone) have been characterised in vitro and in vivo. In each experiment spironolactone was run as a reference. The introduction of the epoxy-group only marginally affected the binding affinity of these compounds for the mineralocorticoid receptor, whereas it caused a decrease for the androgen and progesterone receptors of between 10- and 500-fold. In vivo, all three epoxy-derivatives (3 mg/kg) were potent aldosterone antagonists, 1 to 2 times the potency of spironolactone in the rat. Parallel to the decreased affinity for the androgen and progesterone receptor in vitro, there was a 3- to 10-fold decrease of the antiandrogenic and progestagenic effect compared to spironolactone in the rat and in the rabbit, respectively. Virtually no disturbance of the vaginal or ovulatory cycle was observed with either epoxymexrenone or epoxyprorenone, although epoxyspironolactone caused a 20% decrease in ovulation. It appears therefore that the 9 alpha, 11 alpha-position of the steroid structure is a site of the molecule which can be modified to improve the specificity of aldosterone-antagonists not only in vitro, but also in vivo.