Glucocorticoid receptor antagonism by cyproterone acetate and RU486
Glucocorticoid receptor antagonism by cyproterone acetate and RU486
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DOI：
10.1124/mol.63.5.1012
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发表时间：
2003-05-01
影响因子：
3.6
通讯作者：
Schumacher, C
中科院分区：
文献类型：
--
作者：
Honer, C;Nam, K;Schumacher, C
在糖皮质激素受体（GR）结合化合物的高通量筛选中鉴定了类固醇化合物醋酸环丙孕酮。环丙孕酮（Schering AG）在临床上被用作一种抗雄激素，用于治疗不能手术的前列腺癌、女性男性化综合征和男性性欲抑制。尽管其具有孕酮性质，但环丙孕酮与抗孕酮米非司酮（RU 486; Prossel Uclaf SA）具有相似的药理学特征。环丙孕酮和RU 486对GR和孕酮受体的结合亲和力相似（Kd，15-70 nM）。两种化合物均被表征为地塞米松的竞争性拮抗剂，在大鼠肝细胞中没有内在的反式激活特性（Ki，10-30 nM）。在骨肉瘤细胞中，RU 486显示出比醋酸环丙孕酮更高的效力，以防止地塞米松诱导的GR反式激活和NF κ B反式抑制反应。在施用于Sprague-Dawley大鼠后，发现这两种化合物是口服生物可利用的并且抑制肝脏GR的反式激活。醋酸环丙孕酮和RU 486到GR配体结合结构域的同源模型中的分子对接示出了结合口袋中的重叠类固醇支架。然而，与RU 486相反，环丙孕酮在C11 β位缺乏大的侧链，该侧链被认为通过置换配体结合结构域的C-末端螺旋来触发核受体的主动拮抗作用，从而影响激活功能2。因此，环丙孕酮可能通过最近被描述为被动拮抗的分子机制抑制GR的反式激活。新的治疗方案可能会导致从化合物设计选择性地稳定非活性和活性构象的某些核受体。
The steroid compound cyproterone acetate was identified in a high-throughput screen for glucocorticoid receptor (GR) binding compounds. Cyproterone (Schering AG) is clinically used as an antiandrogen for inoperable prostate cancer, virilizing syndromes in women, and the inhibition of sex drive in men. Despite its progestin properties, cyproterone shares a similar pharmacological profile with the antiprogestin mifepristone (RU486; Roussel Uclaf SA). The binding affinities of cyproterone and RU486 for the GR and progesterone receptor were similar (K-d, 15-70 nM). Both compounds were characterized as competitive antagonists of dexamethasone without intrinsic transactivating properties in rat hepatocytes (K-i, 10-30 nM). In osteosarcoma cells, RU486 revealed a higher potency than cyproterone acetate to prevent responses to dexamethasone-induced GR transactivation and NFkappaB transrepression. Upon administration to Sprague-Dawley rats, both compounds were found to be orally bioavailable and to inhibit transactivation of liver GR. Molecular docking of cyproterone acetate and RU486 into the homology model for the GR ligand binding domain illustrated overlapping steroid scaffolds in the binding pocket. However, in contrast to RU486, cyproterone lacks a bulky side chain at position C11beta that has been proposed to trigger active antagonism of nuclear receptors by displacing the C-terminal helix of the ligand-binding domain, thereby affecting activation function 2. Cyproterone may therefore inhibit transactivation of the GR by a molecular mechanism recently described as passive antagonism. New therapeutic profiles may result from compounds designed to selectively stabilize the inactive and active conformations of certain nuclear receptors.