Different mechanisms for the receptor mediated antimineralocorticoid action of two new spirolactone derivatives.

The introduction of a methoxycarbonyl residue in position 7 of spirolactone produced a molecule (ZK 91587) that exhibited dramatically increased affinity for the rat renal mineralocorticoid receptor (MR) that was lacking in RU 26752 with a propyl group in this same 7 position. The binding of 3H-ZK 91587 was specific to MR in renal cytosol and was not obtained with either serum or cytosol from non-target organs such as liver and lung. The RU 26752-receptor complex was more unstable than aldosterone-MR complex at 35 degrees C but underwent complete thermal activation on DNA cellulose.

Paradoxical differences in the receptor binding of two new antimineralocorticoids.

Two synthetic derivatives of spironolactone were used to examine various aspects of the mineralocorticoid receptor structure and function. Introduction of a propyl residue in the 7-position of spironolactone produced a molecule (RU 26752) that saturated the aldosterone specific receptor in the 1-10 nM range, and another, more abundant species in the 10-100 nM range which had little affinity for the natural hormone. The specificity for both sites was increased when the methoxycarbonyl group was introduced in the 7-position (ZK 91587).