Novel GABA-A Modulators as Cognitive Enhancers

描述（由申请人提供）：作用于3-氨基丁酸a型（GABAA）受体苯二氮卓（BZ）位点的化合物对记忆有深远的影响。例如，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，减弱GABA对受体的作用。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认知增强作用，而没有与非选择性化合物相关的有害副作用。我们的建议将重点放在15GABAA受体上，作为开发治疗阿尔茨海默病的认知增强药物的靶点。这种方法的一个关键原理是，颞叶皮层和相关区域的GABA神经元在阿尔茨海默病患者中大量保留，这些保存的神经元含有15GABAA受体。为了确定用于机制研究的化合物，将采用药物发现方法，在小鼠中进行靶向实验，提出新的化合物，以评估猴子的认知任务。在两个具体目标中，我们将评估以下假设：(1)基于GABAA受体的药效团模型，我们预测15GABAA受体结合袋（L2）特定决定因素活性的增加，以及基于这些化合物的二价配体的产生，将导致具有行为活性的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。这种转化方法应该为识别用于开发阿尔茨海默病和其他认知障碍的认知增强剂的先导化合物提供重要信息。

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.