delta 1-11-oxa-11-deoxycortisol: a new antiglucocorticoid with activity in vivo.
A new steroid-like compound, delta 1-11-oxa-11-deoxycortisol, was tested in a one-week growth suppression, thymus suppression and adrenal weight suppression bioassay for possible glucocorticoid antagonist activity in vivo. We hypothesized that this compound would have antiglucocorticoid activity based on previous studies of 11-deoxycortisol and delta 1,9(11)-11-deoxycortisol, which were optimal glucocorticoid antagonists in vivo in adrenalectomized rats, but which lost antiglucocorticoid activity in intact animals, apparently due to adrenal 11 beta-hydroxylation. Thus, delta 1-11-oxa-11-deoxycortisol, a compound which cannot undergo 11 beta-hydroxylation, was synthesized and tested as an antiglucocorticoid. This analog had an affinity for the rat thymus glucocorticoid receptor similar to that of its parent compounds (Ki 0.9-3.1 x 10(-7) M). A dose of 1 mg/rat antagonized the effect of 15 microgram of dexamethasone in the growth suppression assay (p less than 0.05) and in the thymus suppression assay (p less than 0.06), but did not antagonize dexamethasone-induced adrenal weight suppression. delta 1-11-Oxa-11-deoxycortisol did not exhibit glucocorticoid activity in any of the three assays. These data suggest that delta 1-11-oxa-11-deoxycortisol may be a pure competitive antagonist of dexamethasone.
D015065:17-Hydroxycorticosteroids / Q000494:pharmacology*; D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D003350:Cortodoxone / Q000031:analogs & derivatives / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000378:metabolism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013950:Thymus Gland / Q000502:physiology*
D015065:17-Hydroxycorticosteroids; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; C037607:delta(1)-11-oxa-11-deoxycortisol; D003350:Cortodoxone