Estrogen receptor-β potency-selective ligands:: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues
Estrogen receptor-β potency-selective ligands:: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues
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DOI：
10.1021/jm010254a
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发表时间：
2001-11-22
影响因子：
7.3
通讯作者：
Katzenellenbogen, JA
中科院分区：
文献类型：
--
作者：
Meyers, MJ;Sun, J;Katzenellenbogen, JA
通过努力开发对雌激素受体α（ER α）和β（ER β）具有亚型选择性的新型配体，我们发现2，3-双（4-羟基苯基）丙腈（DPN）对两种ER亚型都起激动剂的作用，但在ER β的转录测定中具有比ER α高70倍的相对结合亲和力和高170倍的相对效力。为了进一步研究这种DPN的ER β亲和性和效力选择性特征，我们制备了一系列DPN类似物，其中配体核心和芳环都通过酚羟基的重新定位和通过添加烷基取代基和腈基来修饰。我们还制备了其他系列的DPN类似物，其中腈官能团被乙炔基或极性官能团取代，以分别模拟腈的线性几何形状或极性。在不同程度上，所有类似物都显示出对ER β的优先结合亲和力（即，它们是ER β亲和选择性的），并且它们中的许多，但不是全部，在通过ER β激活转录方面比通过ER α更有效（即，它们是ER β潜能选择性的）。内消旋-2，3-双（4-羟基苯基）丁二腈和dl-2，3-双（4-羟基苯基）丁二腈是最高的ER β亲和选择性配体，并且它们具有与DPN相当的ER β效力选择性。乙炔类似物具有较高的结合亲和力，但选择性略低于其腈对应物。极性类似物具有较低的亲和力，并且仅氟化极性类似物具有实质性的亲和力选择性。这项研究表明，在这一系列配体中，腈官能团对ER β选择性至关重要，因为它提供了线性几何形状和极性的最佳组合。此外，在DPN的腈上添加第二个腈基β或在β-芳环的邻位添加甲基取代基增加了这些化合物对ER β的亲和力和选择性.这些ER β选择性化合物可能被证明是理解ER α和ER β结构和生物学功能差异的有价值的工具。
Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ER alpha) and beta (ER beta), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ER beta than with ER alpha. To investigate the ER beta affinity- and potency-selective character of this DPN further, we prepared a series of DPN analogues in which both the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and nitrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity for ER beta (i.e., they are ER beta affinity-selective), and many, but not all of them, are also more potent in activating transcription through ER beta than through ER alpha (i.e., they are ER beta potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the, highest ER beta affinity-selective ligands, and they have an ER beta potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogues have lower affinities, and only the fluorinated polar analogues have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ER beta selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group beta to the nitrile in DPN or the addition of a methyl substitutent at an ortho position on the beta -aromatic ring increases the affinity and selectivity of these compounds for ER beta. These ER beta -selective compounds may prove to be valuable tools in understanding the differences in structure and biological function of ER alpha and ER beta.