Phosphodiesterase-2 and Mood Disorders: Target Validation and Drug Discovery

描述（由申请人提供）：本项目的目标是验证磷酸二酯酶-2（PDE 2）作为治疗情绪障碍的药理学靶点，并发现新型选择性抑制剂。PDE 2的抑制通过阻断其水解增强cGMP信号传导，并对行为产生抗焦虑和抗抑郁作用。目前，几乎没有有效的和选择性的PDE 2抑制剂。我们的研究利用高水平的计算分子建模来预测新型PDE 2抑制剂的结构;有些已经合成用于神经药理学和行为学评估。为了推进这一领域的药物发现，提出了以下具体目标：1）设计和合成PDE 2抑制剂，并在体外测试效力和选择性;以及2）确定PDE 2抑制剂的神经化学和行为作用，以及PDE 2的RNAi敲低是否模拟在药理学抑制PDE 2后观察到的抗焦虑和抗抑郁作用。完成拟定的实验将导致确定PDE 2抑制的最佳分子结构，合成有前途的化合物，并验证急性和慢性治疗后的抗焦虑和抗抑郁作用。此外，它将提供PDE 2作为情绪障碍相关靶标的非药理学验证。这最终将导致开发用于治疗焦虑症和抑郁症的新药。此外，成功的交互式分子建模/化学合成/药理学表征模型将为涉及其他PDE家族和其他神经精神药理学适应症的未来药物发现工作提供基础。大多数PDE家族在脑中表达，从CNS药物发现和开发的角度来看，有几个家族似乎具有潜在的意义。为当前PDE 2项目提出的基本原理、策略、方法和分析将为涉及其他PDE家族的未来药物发现工作提供模板，特别是因为PDE抑制已被证明是一种有用的治疗方法（例如，西地那非;即，伟哥）。 公共卫生相关性：焦虑和抑郁等情绪障碍是慢性衰弱性疾病。药物治疗并不是最佳的，因为在许多个体患者中效果不佳，对某些疾病（如PTSD）无效，以及可能导致缺乏依从性的副作用。需要具有新的作用机制的药物，其可以表现出更大的功效和更少的副作用。我们发现磷酸二酯酶-2（PDE 2）抑制剂有望成为抗焦虑和抗抑郁药物。拟议的研究将发现，合成和表征新型PDE 2抑制剂的神经化学和行为效应。这可能会导致识别出一类新的治疗情绪障碍的药物。

DESCRIPTION (provided by applicant): The goal of this project is to validate phosphodiesterase-2 (PDE2) as a pharmacological target for the treatment of mood disorders and to discover novel, selective inhibitors. Inhibition of PDE2 enhances cGMP signaling by blocking its hydrolysis and produces anxiolytic and antidepressant effects on behavior. At present, there are few potent and selective PDE2 inhibitors. Our research has utilized high-level computational molecular modeling to predict structures for novel PDE2 inhibitors; some have been synthesized for neuropharmacological and behavioral evaluation. In order to advance drug discovery in this area, the following specific aims are proposed: 1) Design and synthesize PDE2 inhibitors and test for potency and selectivity in vitro; and 2) Determine the neurochemical and behavioral effects of PDE2 inhibitors and whether RNAi knockdown of PDE2 mimics the anxiolytic and antidepressant effects seen following pharmacological inhibition of PDE2. The completion of the proposed experiments will result in the identification of optimal molecular structures for PDE2 inhibition, synthesis of promising compounds, and verification of anxiolytic and antidepressant effects following both acute and chronic treatment. In addition, it will provide a non-pharmacological validation of PDE2 as a target relevant to mood disorders. This eventually will result in the development of novel drugs for the treatment of anxiety disorders and depression. In addition, the successful interactive molecular modeling/chemical synthesis/pharmacological characterization model will provide the basis for future drug discovery efforts involving other PDE families and other neuropsychopharmacological indications. Most PDE families are expressed in the brain and several appear to be of potential interest from a CNS drug discovery and development perspective. The rationale, strategy, approach, and analysis that are proposed for the present PDE2 project will provide a template for future drug discovery efforts involving other PDE families, especially since PDE inhibition has been shown to be a useful therapeutic approach (e.g., sildenafil; i.e., Viagra). PUBLIC HEALTH RELEVANCE: Mood disorder such as anxiety and depression are chronic debilitating diseases. Pharmacological treatments are not optimal due to poor effects in many individual patients, ineffectiveness for some conditions such as PTSD, and side effects that can cause lack of compliance. There is a need for drugs with novel mechanisms of action that may exhibit greater efficacy and fewer side effects. We have found that inhibitors of phosphodiesterase-2 (PDE2) have promise as anxiolytic and antidepressant drugs. The proposed research will discover, synthesize, and characterize the neurochemical and behavioral effects of novel PDE2 inhibitors. This may result in the identification of a new class of drugs for treating mood disorders.