Δ^1,9(11))-ll-Deoxy cortisol: An Improved Glucocorticoid Antagonist

Previous studies in the rat have demonstrated that 11-deoxycortisol [compound S (pregn-4-ene-17α,21-diol-3,20-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. Δ1,9(11)-ll-Deoxycortisol (pregn-l,4,9(11)-triene-17α,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 Δ1,9(11)-11-deoxycortisol with that of 11-deoxycortisol. The affinity of both compounds for the rat thymus glucocorticoid receptor was similar (equilibrium dissociation constant, 3 × 10-7 M). Both compounds antagonized dexamethasone-induced liver glycogen accumulation in nonadrenalectomized rats, Δ1,9(11)-11-deoxycortisol being 3-fold more potent than 11-deoxycortisol. Neither compound showed agonist activity in this bioassay. Δ1,9(11)-9(11)-11-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. Δ1,9(11)-11-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 Δ1,9(11)-11-deoxycortisol produces metabolites with agonist activity. Δ1,9(11)-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.