Immunophilin Ligands and Age-related Cognition

描述(由申请人提供)：这项工作的最终目标是将一种神经免疫亲和素配体商业化，用于提高慢性神经退行性疾病患者的认知能力。在对老年大鼠和灵长类动物的初步研究中，神经免疫亲和素配体已被证明可以增强空间学习和延迟匹配到样本的表现。然而，其作用机制尚不清楚。在这项第一阶段的可行性研究中，我们建议阐明我们的神经免疫亲和素配体增强认知功能的作用机制。了解这一机制将有助于设计更有效和更有选择性的化合物。神经免疫亲和素配体是一类具有口服活性的小分子物质，在多种神经变性动物模型中起到神经保护作用，促进受损轴突的形态和功能恢复。一种名为GPI 1485的原型化合物目前正在帕金森病的第二阶段人体临床试验中进行评估，每天服用1克，4次。我们建议通过确定神经元中GPI 1485-FKBP复合体的下游结合靶点来解决机制问题。我们建议使用亲和层析和生化技术来确定GPI 1485的直接结合蛋白。我们将通过评估认知增强药物治疗后老年动物的mRNA和蛋白质表达谱来补充这些研究。此外，还将描述FKBP配体利用的不同生物途径。在这些拟议研究成功完成后的未来工作中，我们希望将这些机制信息应用于重新设计、合成和评估具有更强效力、更多类似药物的特性以及更好的选择性和特异性来治疗认知缺陷的化合物。

DESCRIPTION (provided by applicant): The ultimate goal of this work is to commercialize a neuroimmunophilin ligand for cognition enhancement in patients with chronic neurodenerative disease. In preliminary studies in aged rats and primates, neuroimmunophilin ligands have been shown to enhance spatial learning and delayed matching-to-sample performance. However, the mechanism of action is not understood. In this Phase I feasibility study, we propose to elucidate the mechanism of action of the cognition enhancing effects of our neuroimmunophilin iigands. Understanding the mechanism will facilitate the design of more potent and selective compounds. Neuroimmunophilin ligands are orally active small molecules, which provide neuroprotection and stimulate morphologic and functional recovery of injured axons in multiple animal models of neurodegeneration. A prototype compound termed GPI 1485 is currently being evaluated in Phase II human clinical trials for Parkinson's Disease given at 1 gram 4 times per day. We propose to address the question of mechanism by identifying downstream binding targets of the GPI 1485-FKBP complex in neurons. We propose to use affinity chromatography and biochemical techniques to determine direct binding proteins of GPI 1485. We will complement these studies by evaluating mRNA and protein expression profiles in aged animals following cognition-enhancing drug treatment. In addition, the different biologic pathways utilized by FKBP ligands will be characterized. In future work following the successful completion of these proposed studies, we would then like to apply this mechanistic information towards re-designing, synthesizing and evaluating compounds with increased potency, more drug-like properties and better selectivity and specificity to treat cognitive deficits.