Analysis of the relation between receptor binding affinity and antagonist efficacy of antiglucocorticoids.
The biological potencies of four antiglucocorticoids, RU486 (RU), dexamethasone-oxetanone (DOX), R5020, and progesterone have been studied with respect to dexamethasone induction of tyrosine aminotransferase (TAT) in rat hepatoma tissue culture (HTC) cells. Their inhibitory effects in whole-cell competition binding studies (at 37 degrees C) and in TAT induction studies were analyzed by Dixon plots and Schild plots, respectively. We show that: In both cases, there is an actual competition of each antiglucocorticoid with the agonist dexamethasone for the same binding site; the two Kd values derived from the two plots are almost identical for each antiglucocorticoid; RU486 can be distinguished from the three other antiglucocorticoids by its high biological efficacy and its high affinity for the glucocorticoid receptor in whole cells at 37 degrees C (identical to its affinity in cytosol at 0 degree C). These results imply that: There is a linear correlation between the antagonist efficacies of antiglucocorticoids and their affinities for the glucocorticoid receptor in whole cells at 37 degrees C; the antagonistic action is solely mediated by competition with the agonist for the receptor binding site; this is verified by the fact that in all cases, in the presence or absence of antiglucocorticoids, a specific TAT induction level was always related to the same level of receptor saturation by the agonist in whole cells; the phenomena responsible for the high antagonist efficacy of RU486 are also responsible for its high affinity in whole cells at 37 degrees C.
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003907:Dexamethasone / Q000031:analogs & derivatives / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D008433:Mathematics; D015735:Mifepristone; D011374:Progesterone / Q000494:pharmacology; D011397:Promegestone / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D014444:Tyrosine Transaminase / Q000378:metabolism
D004963:Estrenes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C041706:dexamethasone oxetanone; D011374:Progesterone; D003907:Dexamethasone; D011397:Promegestone; D014444:Tyrosine Transaminase