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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor
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Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor

机译：选择性变构增强剂对EP2前列腺素受体的神经保护作用

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摘要

Activation of the Gas-coupled EP2 receptor for prostaglandin E2 (PGE_2) promotes cell survival in several models of tissue damage. To advance understanding of EP2 functions, we designed experiments to develop allosteric potentiators of this key prostaglandin receptor. Screens of 292,000 compounds identified 93 that at 20 nM (i) potentiated the cAMP response to a low concentration of PGE_2 by > 50%; (ii) had no effect on EP4 or β2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE_2 on EP2 receptors at least 3-fold. In aqueous solution, the active compounds are largely present as nanoparticles that appear to serve as active reservoirs for bioactive monomer. From 94 compounds synthesized or purchased, based on the modification of one hit compound, the most active increased the potency of PGE_2 on EP2 receptors 4- to 5-fold at 10 to 20 μM and showed substantial neuroprotection in an excito-toxicity model. These small molecules represent previously unde-scribed allosteric modulators of a PGE_2 receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE_2 released in a cell-injury setting is neuroprotective.
机译：前列腺素E2（PGE_2）的气体偶联EP2受体的激活可在几种组织损伤模型中促进细胞存活。为了增进对EP2功能的了解，我们设计了实验来开发这种关键前列腺素受体的变构增强剂。对292,000种化合物的筛选确定了93种在20 nM时（i）增强了cAMP对低浓度PGE_2的响应> 50％； （ii）对EP4或β2肾上腺素能受体，cAMP分析本身或亲本细胞系没有影响； （iii）将PGE_2对EP2受体的效力提高至少3倍。在水溶液中，活性化合物主要以纳米颗粒的形式存在，似乎可以充当生物活性单体的活性储库。基于一种命中化合物的修饰，从94种合成或购买的化合物中，最具活性的PGE_2对EP2受体的效力在10至20μM时提高了4至5倍，并在兴奋毒性模型中显示出实质性的神经保护作用。这些小分子代表以前未描述的PGE_2受体的变构调节剂。我们的研究结果强烈证实了在细胞损伤环境中释放的内源性PGE_2对EP2受体的激活具有神经保护作用。

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    Jianxiong Jiang; Thota Ganesh; Yuhong Du; Pahk Thepchatri; Asheebo Rojas; Iestyn Lewis; Serdar Kurtkaya; Lian Li; Min Qui; Geidy Serrano; Renee Shaw; Aiming Sun; Ray Dingledine;

  • 作者单位

    Department of Pharmacology,Emory University, Atlanta, GA 30322;

    rnDepartment of Chemistry, Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Chemistry, Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Chemistry, Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322;

    rnDepartment of Pharmacology,Emory University, Atlanta, GA 30322;

    rnDepartment of Chemistry, Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

    rnDepartment of Chemistry, Emory University, Atlanta, GA 30322 Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    excitotoxicity; neuronal injury; prostaglandin E2; time-resolved fluorescence resonance energy transfer; ultra high-throughput screening;

    机译：兴奋性毒性神经元损伤前列腺素E2;时间分辨荧光共振能量转移;超高通量筛选;

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