Δ1, 9(11))-11-deoxy cortisol: An improved glucocorticoid antagonist

George P. Chrousos, Kevin M. Barnes, Mark A. Sauer, D. Lynn Loriaux, Gordon B. Cutler

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)472-477
Number of pages6
JournalEndocrinology
Volume107
Issue number2
DOIs
StatePublished - Aug 1980

ASJC Scopus subject areas

  • Endocrinology

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    Chrousos, G. P., Barnes, K. M., Sauer, M. A., Loriaux, D. L., & Cutler, G. B. (1980). Δ1, 9(11))-11-deoxy cortisol: An improved glucocorticoid antagonist. Endocrinology, 107(2), 472-477. https://doi.org/10.1210/endo-107-2-472