Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.
Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.
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DOI：
10.1021/cn100106a
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发表时间：
2011-05-18
影响因子：
5
通讯作者：
Thatcher, Gregory R. J.
中科院分区：
文献类型：
--
作者：
Abdelhamid, Ramy;Luo, Jia;VandeVrede, Lawren;Kundu, Indraneel;Michalsen, Bradley;Litosh, Vladislav A.;Schiefer, Isaac T.;Gherezghiher, Teshome;Yao, Ping;Qin, Zhihui;Thatcher, Gregory R. J.
本研究比较了临床应用的苯并噻呋SERM（BT-SERM）雷洛昔芬与雌激素对原代大鼠神经元氧糖剥夺（OGD）的保护作用。确定了一个BT-SERM家族的神经保护结构-活性关系，该家族显示出一系列ERα和ERβ结合亲和力和激动剂/拮抗剂活性，从而发现了一种神经保护药效团，存在于临床相关的SERM、雷洛昔芬和去甲基阿佐昔芬（DMA）中，观察到其亚微摩尔的神经保护效力。BT-SERM神经保护与ER结合或经典ER活性无关，然而，使用药理学探针显示神经保护性SERM和雌激素均激活相同的激酶信号级联。抗雌激素ICI 182，780抑制雌激素的作用，但不抑制BT-SERM的作用，而G蛋白偶联受体GPR 30的拮抗作用对SERM和雌激素均有效。由于SERMs具有抗氧化活性，因此使用经典的酚类抗氧化剂BHT和Trolox以及Nrf 2依赖性细胞保护亲电试剂萝卜硫素研究了ER独立机制。然而，这些药物的神经保护作用对GPR 30拮抗作用不敏感。总的来说，这些数据表明，神经保护BT-SERMs的活性是GPR 30依赖性和ER非依赖性的，不受抗氧化作用的介导。新的BT-SERM衍生物和类似物的比较确定了一种潜在的神经保护药效团，可用于设计具有ER活性谱的新型神经保护剂。
The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agonist/antagonist activity, leading to discovery of a neuroprotective pharmacophore, present in the clinically relevant SERMS, raloxifene and desmethylarzoxifene (DMA), for which submicromolar potency was observed for neuroprotection. BT-SERM neuroprotection did not correlate with binding to ER nor classical ER activity, however, both the neuroprotective SERMs and estrogens were shown, using pharmacological probes, to activate the same kinase signaling cascades. The antiestrogen ICI 182,780 inhibited the actions of estrogens, but not those of BT-SERMs, whereas antagonism of the G-protein coupled receptor, GPR30, was effective for both SERMs and estrogens. Since SERMs have antioxidant activity, ER-independent mechanisms were studied using the classical phenolic antioxidants, BHT and Trolox, and the Nrf2-dependent cytoprotective electrophile, sulforaphane. However, neuroprotection by these agents was not sensitive to GPR30 antagonism. Collectively, these data indicate that the activity of neuroprotective BT-SERMs is GPR30-dependent and ER-independent and not mediated by antioxidant effects. Comparison of novel BT-SERM derivatives and analogs identified a neuroprotective pharmacophore of potential use in design of novel neuroprotective agents with a spectrum of ER activity.
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影响因子：
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作者：
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通讯作者：
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