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用于慢性神经退行性疾病患者认知增强的神经亲免疫素配体商业化。在老年大鼠和灵长类动物的初步研究中，神经亲免疫素配体已被证明可以增强空间学习和延迟匹配样本的表现。然而，其作用机制尚不清楚。在本一期可行性研究中，我们拟阐明亲神经免疫蛋白配体增强认知作用的作用机制。了解这一机制将有助于设计出更有效、更有选择性的化合物。神经亲免疫素配体是一种具有口服活性的小分子，在多种神经变性动物模型中具有神经保护作用，并刺激损伤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II期人体临床试验中进行评估，每天给药4次，每次1克。我们建议通过识别神经元中GPI 1485-FKBP复合物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和蛋白表达谱来补充这些研究。此外，FKBP配体利用的不同生物学途径将被表征。在成功完成这些研究后的未来工作中，我们希望将这些机制信息应用于重新设计、合成和评估具有更高效力、更像药物性质、更好选择性和特异性的化合物，以治疗认知缺陷。

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.