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Neurotrophic estrogens: essential profile and endpoints for drug discovery().

机译:神经营养性雌激素:药物发现的基本概况和终点。

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Criteria for the early recognition of selective neurotrophic action are crucial for the discovery of estrogens for supplementation therapy. The comparative characterization of 'tool' compounds in different paradigms demonstrates that estrogen-mediated CNS effects are discernible before the manifestation of changes in primary target organs. Agonist activity at, and recruitment of the coactivator SRC-1 by, the estrogen receptor alpha accurately reflect peripheral, but not neurotrophic, efficacy. Interaction with, and SRC-1 recruitment at, the estrogen receptor beta appears to be an essential prerequisite for pronounced CNS effects. Monitoring of the hypothalamo-pituitary-adrenal axis activity and the differential organ-specific induction of estrogen-responsive proteins are helpful for early delineation of CNS efficacy. Behavioral and antioxidant efficacy are useful confirmatory readouts, with limited roles in lead selection. Finally, an algorithm for the identification of estrogens with a neurotrophic profile can be generated by assigning 'performance grades' in a multifarious test array.
机译:早期识别选择性神经营养作用的标准对于发现补充疗法的雌激素至关重要。在不同范式中“工具”化合物的比较特征表明,在主要靶器官变化出现之前,雌激素介导的中枢神经系统作用是可辨别的。雌激素受体α处的激动剂活性和辅激活物SRC-1的募集准确反映了外周但非神经营养的功效。与雌激素受体β的相互作用以及SRC-1的募集似乎是明显的中枢神经系统作用的必要先决条件。监测下丘脑-垂体-肾上腺轴活性和雌激素应答蛋白的器官特异性差异诱导有助于中枢神经系统疗效的早期描述。行为和抗氧化剂功效是有用的确认性读数,在铅选择中的作用有限。最后,可以通过在各种测试阵列中分配“性能等级”来生成用于识别具有神经营养特征的雌激素的算法。

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