THE SECOND BINDING SITE ON THE GLUCOCORTICOID RECEPTOR

首席调查员有证据表明糖皮质激素受体 含有第二个激素结合部位。它的存在一直是 通过测量拮抗剂类固醇对大鼠心脏功能的影响 激动剂与糖皮质激素受体解离。最近的初步调查 有证据表明，酮康唑，一种非甾体化合物也 与此站点的交互和其他新结果表明此站点可能 控制激动剂-受体复合体的转化。因为 此站点的特殊性假设此“监管”站点 调解对手的行动。 这些研究的目标是更全面地描述这一秒， 糖皮质激素受体上的非糖皮质激素结合部位。八 已经制定了具体目标。1.进一步证明存在 这是糖皮质激素受体每种形式上的第二个位点 (已变换和未变换)。2.其在糖皮质激素中的位置 将对受体进行研究。3.化学环境和结合 这个网站的偏好将是详细的。4.相互作用 具有第二个位置的非甾体化合物将被评估，以便 确定其中任何一个是否具有独特的亲和力。5.更新，速度更快 受体分析技术(高效液相色谱法和垂直管法 超速离心法)将用于研究其疗效 受体结构上的抗糖皮质激素。6. 对转化后的抗糖皮质激素进行定量。7.搜查 将为其他类固醇激素受体上的类似结合部位制作。 8.将在act-20中评估抗糖皮质激素的生物潜力。 手机。 这项研究的意义在于它有可能开发出一种 抗糖皮质激素作用的可靠理论。这反过来又会 导致更有效的方法来识别临床上有意义的药物。 预计这些化合物不仅在治疗方面将发挥重要作用 糖皮质激素过量的状态，也可以作为免疫调节剂 用于治疗恶性肿瘤。

The Principal Investigator has evidence that the glucocorticoid receptor contains a second hormone binding site. Its existence has been demonstrated by measuring the effect of antagonist steroids on the rate of agonist dissociation from the glucocorticoid receptor. Recent preliminary evidence suggests that ketoconazole, a non-steroidal compound also interacts with this site and other new results suggest that this site may control transformation of agonist-receptor complexes. Because of the specificity of this site it is hypothesized that this "regulatory" site mediates antagonist action. The goal of these studies is to characterize more fully this second, nonglucocorticoid binding site on the glucocorticoid receptor. Eight Specific Aims have been formulated. 1. to document further the presence of this second site on each of the forms of the glucocorticoid receptor (transformed and untransformed). 2. its location along the glucocorticoid receptor will be investigated. 3. the chemical milieu and binding preference of this site will be detailed. 4. the interaction of non-steroidal compounds with this second site will be assessed in order to determine whether any possess unique affinity. 5. newer, more rapid techniques of receptor analysis (HPLC and vertical tube ultracentirfugation) will be applied to investigate the effect of antiglucocorticoids on receptor structure. 6. the effect of antiglucocorticoids on transformation will be quantitated. 7. a search will be made for similar binding sites on other steroid hormone receptors. 8. the biopotency of antiglucocorticoids will be assessed in the AcT-20 cell. The significance of this research lies in its potential for developing a reliable theory of antiglucocorticoid hormone action. This, in turn, will lead to more effective ways of identifying clinically significant agents. It is expected that these compounds will be important not only in treating states of glucocorticoid excess but also as immunoregulators that can be used in treating malignancies.