A-ll-Deoxy cortisol: An Improved Glucocorticoid Antagonist

Previous studies in the rat have demonstrated that 11-deoxycortisol [compound S (pregn-4-ene-17a,21-diol3,20-dione)], a competitive glucocorticoid antagonist in vitro, fails to behave as an antagonist in growth and adrenal suppression bioassays in nonadrenalectomized animals. This is probably explained by conversion of 11-deoxycortisol to cortisol by the adrenal glands. A'-ll-Deoxycortisol (pregn-l,4,9(l>l)-triene17a,21-diol-3,20 dione) has been shown to resist 11-hydroxylation because of the double bond at the 9-11 position and, hence, should be a more effective antiglucocorticoid in vivo. This hypothesis was tested by comparing the in vivo antiglucocorticoid activity of A'-ll-deoxycortisol with that of 11-deoxycortisol. The affinity of both compounds for the rat thymus glucocorticoid receptor was similar (equilibrium dissociation constant, 3 X 10' M). Both compounds antagonized dexamethasone-induced liver glycogen accumulation in nonadrenalectomized rats, A ' -11deoxycortisol being 3-fold more potent than 11-deoxycortisol. Neither compound showed agonist activity in this bioassay. A-ll-Deoxycortisol showed partial agonist-antagonist activity in 1-week growth suppression and thymus suppression assays, while 11-deoxycortisol behaved as a glucocorticoid agonist. Both compounds failed to antagonize dexamethasone and acted as agonists of equal potency in a 1-week adrenal suppression assay. A-ll-Deoxycortisol, administered to adrenalectomized rats, lost all its agonist activity in the growth suppression assay and exhibited only antagonist activity. These observations suggest that adrenal 11-hydroxylation of both 11-deoxycortisol and A''-ll-deoxycortisol produces metabolites with agonist activity. A-ll-Deoxycortisol retains antagonist activity, probably because conversion to the agonist metabolite is less complete and its intrinsic antagonist activity is greater. These observations support the hypothesis that analogs of 11-deoxycortisol with increased resistance to 11-hydroxylation will have increased antiglucocorticoid activity in intact (nonadrenalectomized) animals. (Endocrinology 107: 472,1980) C useful antagonists for mineralocorticoids, estrogens, and androgens have been in use for many years (1-3). An effective glucorticoid antagonist, however, has not as yet been developed. Since the discovery of the antiglucocorticoid properties of progesterone in the 1960s (4, 5), many steroidal compounds have been reported to antagonize glucocorticoid activity in in vitro test systems (6-10), and their mechanism of action has been extensively studied in vitro (6, 11-13). The in vitro antiglucocorticoids lack the 11-/?hydroxyl group (4-9), except for the 17/8-carboxamide derivatives (10). Attempts to show in vivo antiglucocorticoid activity with 11-deoxycortisol, an effective antiglucocorticoid in Received October 22,1979. Address requests for reprints to: Dr. George P. Chrousos, National Institutes of Health, Building 10, Room 10B09, Bethesda, Maryland 20205. * Ph.D. candidate at George Washington University Department of Pharmacology at the time this work was completed. 1 The following abbreviations are used: 11-deoxycortisol (compound S), pregn-4-ene-17a,21-diol; A-'11-deoxycortisol, pregn-l,4,9(ll)triene-17a,21-diol-3,20-dione; dexamethasone, 9a-fluoro-16a-methylpregna-l,4-diene-ll/U7a,21-triol-3,20-dione. vitro (6,-9, 11-13), initially yielded conflicting results (14-17). We postulated that in vivo 11-hydroxylation of 11-deoxycortisol might explain its failure under certain conditions (14, 15) to behave as a glucocorticoid antagonist (18). Since the ll-/?-hydroxylase system, except in rare cases of gonadal tumors (19, 20), has been found to occur only in the adrenal glands (21), 11-deoxycortisol was tested in adrenalectomized rats and was shown to be a pure antagonist of dexamethasone (18). However, 11deoxycortisol failed to antagonize dexamethasone in intact rats and, in fact, it exhibited glucocorticoid agonist activity. This was attributed to its conversion to cortisol by adrenal 11-hydroxylation (18). These observations suggested that analogs of 11-deoxycortisol resistant to 11-hydroxylation might have increased antiglucocorticoid activity in vivo. The current study tests this hypothesis by comparing the in vivo antiglucocorticoid activity of 11-deoxycortisol and A-ll-deoxycortisol, an analog which has been shown to be metabolized in vitro by 11-hydroxylase approximately 5-10% as rapidly as 11-deoxycortisol (22-24).