Abstract
[3H]RU 486 competes with dexamethasone for rat kidney glucocorticoid receptor (GR) occupancy in vitro, exhibiting a higher association constant for binding to GR than [3H] dexamethasone. Unlike [3H]dexamethasone-receptor complexes which dissociate rapidly at 37 degrees C even in the presence of molybdate, [3H]RU 486-receptor complexes remained more stable both in the presence and in the absence of molybdate. Interestingly, sulfhydryl reagents such as N-ethylmaleimide, iodoacetamide and tosyllysyl chloromethane at 5mM concentration almost completely inhibited binding of [3H]dexamethasone to GR, whereas 20-30% binding to [3H]RU 486 was inhibited by these reagents. [3H]RU 486-receptor complexes readily undergo temperature-dependent activation in vitro as judged by their binding to DNA-cellulose. We propose that changes in binding affinity, stability and sulfhydryl reagent sensitivity between glucocorticoid agonist and antagonist may be due to subtle differences in the binding of the agonist and antagonist to the steroid binding domain of the receptor. This may have a direct relevance to the antiglucocorticoid properties of RU 486.
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