GABA-A alpha5 cognitive enhancers: pharmacology and neuropsychology in macaques

描述（由申请人提供）：认知障碍是阿尔茨海默病和轻度认知障碍的一种使人衰弱的结果。认知障碍降低了生活质量，增加了治疗费用。认知功能的相对适度提高会使生活质量相对大幅提高，并大幅降低护理成本。增强认知功能的姑息治疗将使许多患者受益，直到开发出针对其潜在疾病的治疗方法。这种认知增强剂的一个有希望的药理学靶点是γ-氨基丁酸（GABA）A型（GABAA）受体复合物上的苯二氮杂卓（BZ）结合位点。已经开发了GABAAa 5-BZ受体（GABAAa 5- BZr）的亚型选择性配体，GABAAa 5- BZr主要在海马中表达，海马是记忆功能的重要部位。啮齿动物和非人灵长类动物记忆测定的研究表明，GABAAa 5-BZr反向激动剂改善认知，副作用很少。在拟定的研究中，将对8只恒河猴进行训练，以执行CANTAB非人灵长类动物神经心理测试组合的测试。还将对4只猴进行延迟样本匹配试验培训，并植入无线电遥测装置，以测量剂量范围研究的心血管和呼吸反应。剂量范围队列将确定化合物在灵长类动物中的活性剂量，并在CANTAB训练的猴子中进行全面认知测试之前筛选产生不良反应的化合物。在剂量范围或CANTAB训练的猴中测试之前，将在小鼠中测试新化合物的毒性。GABAAa 5-BZr配体对猕猴认知功能的影响将通过GABAAa 5-BZr激动剂、拮抗剂和反向激动剂的预处理来确定。这些研究将检验GABAAa 5-BZr的活性可以双向调节认知的假设，其中激动剂损害认知表现，而反向激动剂增强表现。CANTAB神经心理学成套测试的区域特异性还将允许测试以下假设：GABAAa 5-BZr认知调节将发生在由颞脑结构（即海马体）介导的测试中，而不是由额叶皮质结构介导的测试中。此外，GABAAa 5-BZr反向激动剂逆转东莨菪碱诱导的认知损害的能力将决定这些化合物作为治疗阿尔茨海默病产生的认知损害的潜在有效性。理解GABAAa 5-BZr配体的作用对认知的神经药理学、神经心理学和神经解剖学具有重要意义，并且将进一步开发用于阿尔茨海默病和轻微认知损害中的认知功能障碍的新型治疗剂。

DESCRIPTION (provided by applicant): Cognitive impairment is a debilitating outcome of Alzheimer's Disease and Minor Cognitive Impairment. Cognitive impairment reduces quality of life and increases treatment costs. Relatively modest increases in cognitive function produce relatively large increases in quality of life and large decreases in cost of care. Palliative treatments enhancing cognitive function would benefit many patients until treatments for their underlying disorders are developed. One promising pharmacological target for such cognitive enhancers is the benzodiazepine (BZ) binding site on the gamma-aminobutyric acid (GABA) type A (GABAA) receptor- complex. Subtype-selective ligands have been developed for the GABAA-a5 BZ receptor (GABAAa5- BZr), which is predominately expressed in the hippocampus, a site important for memory function. Studies in rodent and nonhuman primate memory assays indicate that GABAAa5-BZr inverse agonists improve cognition with few adverse effects. In the proposed studies, 8 rhesus monkeys will be trained to perform tests from the CANTAB nonhuman primate neuropsychological testing battery. 4 monkeys will be also be trained on the delayed-match-to- sample test and implanted with radio-telemetry devices to measure cardiovascular and respiratory responses for dose-ranging studies. The dose-ranging cohort will determine active doses of the compounds in primates and also screen for compounds producing adverse effects prior to full cognitive testing in the CANTAB-trained monkeys. Novel compounds will be tested for toxicity in mice prior to testing in the dose- ranging or CANTAB-trained monkeys. The effects of GABAAa5-BZr ligands on cognitive function in macaques will be determined by pretreatments of GABAAa5-BZr agonists, antagonists and inverse agonists. These studies will test the hypothesis that activity at the GABAAa5-BZr can bi-directionally modulate cognition with agonists impairing cognitive performance and inverse agonists enhancing performance. The regional specificity of the CANTAB neuropsychological test battery will also allow for testing of the hypothesis that GABAAa5-BZr cognitive modulation will occur in tests mediated by temporal brain structures (i.e. the hippocampus) as opposed to tests mediated by frontal cortical structures. In addition, the ability of GABAAa5-BZr inverse agonists to reverse scopolamine-induced cognitive impairment will determine the potential effectiveness of these compounds as treatments for the cognitive impairment produced by Alzheimer's disease. Understanding the effects of GABAAa5-BZr ligands has important implications to the neuro- pharmacology, neuropsychology and neuroanatomy of cognition and will further development of a novel class of therapeutics for cognitive dysfunction in Alzheimer's disease and Minor Cognitive Impairment.