Novel GABA-A Modulators as Cognitive Enhancers

描述(申请人提供)：作用于3-氨基丁酸A型(GABAA)受体的苯二氮卓类(BZ)位置的化合物对记忆有深远的影响。例如，有越来越多的证据表明，BZ位点反向激动剂可以作为认知增强剂发挥作用，这种反向激动剂可以减弱GABA在受体上的作用。特别是，对含有15个亚基的GABAA受体具有选择性的化合物似乎具有增强认知的作用，而没有与非选择性化合物相关的不良副作用。我们的提案将重点放在15GABAA受体上，作为开发治疗阿尔茨海默病的认知增强剂的靶点。这种方法的一个关键原理是，阿尔茨海默病患者的颞叶皮质和相关区域的GABA神经元基本上得到了保存，而这些保存下来的神经元含有15GABAA受体。为了识别用于机制研究的化合物，将使用一种药物发现方法，在小鼠身上进行有针对性的实验，使新化合物在猴子认知任务中进行评估。在两个特定的目标下，我们将评估下列假设：(1)基于GABAA受体的药效团模型，我们预测增加15GABAA受体结合口袋(L2)特定决定因素的活性以及基于这些化合物的二价配体将导致行为活跃的15GABAA受体选择性配体；(2)我们预测15GABAA受体的反向激动剂作用将提高猴子和转基因(APPswe Tg2576)小鼠在认知任务中的表现。这种翻译方法应该为确定先导化合物作为阿尔茨海默病和其他认知障碍的认知增强剂的发展提供重要信息。 与公共卫生相关：阿尔茨海默病是一种慢性、进行性、最终致命的神经退行性疾病，目前几乎没有广泛有效的治疗选择。这项应用的总体目标是探索新化合物的潜力，这种化合物作用于一种名为“GABA受体”的大脑蛋白质，以增强认知功能。由于这些化合物似乎非常安全，它们可能会为治疗与阿尔茨海默氏症和其他相关疾病相关的记忆衰退提供一种很有前途的新方法。

DESCRIPTION (provided by applicant): Compounds that act at the benzodiazepine (BZ) site of the 3-aminobutyric acid type-A (GABAA) receptor have profound effects on memory. For example, there is accumulating evidence that BZ-site inverse agonists, which attenuate GABA's action at the receptor, can act as cognitive enhancing agents. In particular, compounds with selectivity for 15 subunit-containing GABAA receptors appear to have cognition-enhancing effects without the unwanted side effects associated with non-selective compounds. Our proposal will focus on 15GABAA receptors as a target site for developing cognitive enhancing agents for treating Alzheimer's disease. A key rationale for this approach is that GABA neurons in the temporal cortex and associated areas are largely preserved in patients with Alzheimer's disease, and these preserved neurons contain 15GABAA receptors. In order to identify compounds for mechanistic studies, a drug discovery approach will be used in which targeted experiments in mice advance new compounds for evaluation in monkey cognition tasks. In two specific aims, we will evaluate the following hypotheses: (1) Based on a pharmacophore model of GABAA receptors, we predict that increasing activity at specific determinants of the 15GABAA receptor binding pocket (L2), as well as creation of bivalent ligands based on these compounds, will result in behaviorally-active, 15GABAA receptor-selective ligands; and (2) we predict that inverse agonist action at 15GABAA receptors will enhance performance in cognitive tasks in monkeys and transgenic (APPSwe Tg2576) mice. This translational approach should provide important information for identifying lead compounds for development as cognitive enhancing agents for Alzheimer's disease and other cognitive disorders. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a chronic, progressive, and ultimately fatal neurodegenerative disease, and there currently are few broadly effective treatment options. The overall goal of this application is to explore the potential for new compounds, acting at a brain protein called the "GABA receptor", to enhance cognitive function. Because these compounds appear to be remarkably safe, they may provide a promising new approach for treating memory decline associated with Alzheimer's and other related disorders.