Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies.

Corticosterone regulates a wide range of physiological parameters. Two receptors for corticosterone have been identified, the mineralocorticoid (type I) receptor (MR) and the glucocorticoid (type II) receptor (GR). To determine the relative role of these two receptors in mediating the effects of endogenous corticosterone, many studies have relied on the use of putative selective corticosteroid receptor antagonists. This study further examined the in vivo receptor selectivity of two compounds, RU28318 and RU40555 that are believed to be selective antagonists for MR and GR, respectively. Acute treatment of adrenalectomized rats with RU28318 (10-50 mg/kg) selectively decreased ex-vivo available MR binding in the hippocampus, whereas acute treatment with RU40555 (10-30 mg/kg) selectively decreased available GR binding in the hippocampus and pituitary. These receptor binding measures suggest that RU28318 in vivo selectively occupied MR, and that RU40555 in vivo selectively occupied GR. In functional studies, RU28318 (50 mg/kg) blocked the normalizing effect of aldosterone (120 microg/kg) on saline intake of adrenalectomized rats. RU40555 (30 mg/kg) blocked the suppressive effect of dexamethasone (50 microg/kg) on acute stress-induced corticosterone secretion. These studies further support the in vivo corticosteroid receptor selectivity of these two compounds and confirms their effective corticosteroid antagonistic properties.