Chrousos G P, Sauer M A, Loriaux D L, Cutler G B
Steroids. 1982 Oct;40(4):425-31. doi: 10.1016/0039-128x(82)90020-4.
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.
一种新的类固醇样化合物δ1-11-氧杂-11-脱氧皮质醇，在为期一周的生长抑制、胸腺抑制和肾上腺重量抑制生物测定中进行了测试，以检测其在体内可能的糖皮质激素拮抗剂活性。我们基于先前对11-脱氧皮质醇和δ1,9(11)-11-脱氧皮质醇的研究提出假设，即该化合物具有抗糖皮质激素活性。在肾上腺切除的大鼠体内，这两种化合物是最佳的糖皮质激素拮抗剂，但在完整动物中失去了抗糖皮质激素活性，显然是由于肾上腺11β-羟化作用。因此，合成了一种不能进行11β-羟化的化合物δ1-11-氧杂-11-脱氧皮质醇，并将其作为抗糖皮质激素进行测试。该类似物对大鼠胸腺糖皮质激素受体的亲和力与其母体化合物相似（Ki为0.9 - 3.1×10(-7)M）。在生长抑制试验（p＜0.05）和胸腺抑制试验（p＜0.06）中，1mg/大鼠的剂量可拮抗15μg地塞米松的作用，但不能拮抗地塞米松诱导的肾上腺重量抑制。δ1-11-氧杂-11-脱氧皮质醇在这三种试验中均未表现出糖皮质激素活性。这些数据表明，δ1-11-氧杂-11-脱氧皮质醇可能是地塞米松的一种纯粹竞争性拮抗剂。
