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(PDE2)作为治疗情绪障碍的药理靶点，并发现新的、选择性的抑制剂。抑制PDE2通过阻断cGMP的水解酶来增强cGMP信号，并在行为上产生抗焦虑和抗抑郁的效果。目前，有效的、选择性的PDE2抑制剂很少。我们的研究利用高级计算分子模型来预测新型PDE2抑制剂的结构；一些已经被合成用于神经药理学和行为评估。为了促进这一领域的药物开发，提出了以下具体目标：1)设计和合成PDE2抑制剂，并在体外测试其效力和选择性；2)确定PDE2抑制剂的神经化学和行为效应，以及PDE2的RNAi敲除是否模仿PDE2的抗焦虑和抗抑郁作用。拟议实验的完成将导致确定抑制PDE2的最佳分子结构，合成有希望的化合物，并验证急性和慢性治疗后的抗焦虑和抗抑郁效果。此外，它将提供PDE2作为与情绪障碍相关的靶点的非药理学验证。这最终将导致治疗焦虑症和抑郁症的新药的开发。此外，成功的交互分子建模/化学合成/药理学表征模型将为未来涉及其他PDE家族和其他神经精神药理学适应症的药物发现工作提供基础。大多数PDE家族在大脑中表达，从中枢神经系统药物发现和开发的角度来看，有几个似乎是潜在的兴趣。为目前的PDE2项目提出的理论基础、策略、方法和分析将为未来涉及其他PDE家族的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疾病。药物治疗并不是最理想的，因为许多个体患者的效果不佳，对某些情况如创伤后应激障碍无效，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，这些药物可能表现出更好的疗效和更少的副作用。我们发现，磷酸二酯酶-2(PDE2)抑制剂作为抗焦虑和抗抑郁药物具有广阔的应用前景。这项拟议的研究将发现、合成和表征新型PDE2抑制剂的神经化学和行为效应。这可能会导致发现一类治疗情绪障碍的新药物。

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.