Duax W L, Griffin J F, Weeks C M, Wawrzak Z
Medical Foundation of Buffalo, Inc., NY 14203.
J Steroid Biochem. 1988 Oct;31(4B):481-92. doi: 10.1016/0022-4731(88)90002-7.
Examination of the structures of compounds having high affinity for estrogen, progestin, mineralocorticoid and glucocorticoid receptors strongly suggests that receptor binding is primarily the result of a tight association between the receptor and the steroidal A-ring. High affinity binding to the estrogen receptor appears to be dependent upon the presence of a phenolic ring in the substrate. An inverted 1 beta, 2 alpha conformation of the 4-ene-3-one A-ring appears to be most conductive to high affinity binding to the progesterone receptor. Binding to the mineralocorticoid receptor appears to be correlated to a complementary fit between amino acids of the receptor site and a flat 4-en-3-one A-ring similar to that imposed upon aldosterone by the 11,18-epoxide formation. The glucocorticoid receptor appears to prefer a 4-en-3-one A-ring that is bowed toward the alpha-face as is the case in structures having a 9 alpha-fluoro substituent or additional unsaturation at C(1)-C(2). The binding of androgens to their receptor differs in appearing to have an essential dependence upon functional groups at the A- and D-ring end of the steroid. With the exception of the androgens, the data suggest that specific interactions between the steroid B-, C- and D-rings and the receptor play at best a minor role in receptor binding but are the most important factor in determining agonist versus antagonist behavior subsequent to binding. Antagonists that compete for a steroid receptor site may be expected to have the A-ring composition and conformation necessary for receptor binding but lack the 11 beta-OH and the D-ring conformational features and functional groups that induce or stabilize subsequent receptor functions. Antagonists might also be compounds with A-ring conformations appropriate for binding but other structural features that interfere with subsequent receptor functions essential to activity.
对与雌激素、孕激素、盐皮质激素和糖皮质激素受体具有高亲和力的化合物结构进行研究，结果强烈表明，受体结合主要是受体与甾体A环紧密结合的结果。与雌激素受体的高亲和力结合似乎取决于底物中酚环的存在。4-烯-3-酮A环的1β,2α反向构象似乎最有利于与孕激素受体的高亲和力结合。与盐皮质激素受体的结合似乎与受体位点氨基酸与扁平的4-烯-3-酮A环之间的互补契合相关，这种契合类似于醛固酮形成11,18-环氧化物时所呈现的构象。糖皮质激素受体似乎更喜欢4-烯-3-酮A环向α面弯曲的结构，就像在具有9α-氟取代基或C(1)-C(2)处额外不饱和键的结构中那样。雄激素与其受体的结合有所不同，似乎主要依赖于甾体A环和D环末端的官能团。除雄激素外，数据表明甾体B环、C环和D环与受体之间的特定相互作用在受体结合中充其量只起次要作用，但在决定结合后激动剂与拮抗剂行为方面却是最重要的因素。预计竞争甾体受体位点的拮抗剂具有受体结合所需的A环组成和构象，但缺乏诱导或稳定后续受体功能的11β-OH以及D环构象特征和官能团。拮抗剂也可能是具有适合结合的A环构象但其他结构特征会干扰后续对活性至关重要的受体功能的化合物。
