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

磷酸二酯酶 2 和情绪障碍：靶标验证和药物发现

基本信息

批准号：
7824456
负责人：
JAMES M O'DONNELL
金额：
$ 48.33万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7824456
关键词：
Acute Address Adverse effects Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Area Arts Behavior Behavioral Brain Chronic Cyclic GMP Data Development Disease Evaluation Exhibits Family Future Goals Guanylate Cyclase Hydrolysis In Vitro Individual Lead Lentivirus Vector Mediating Modeling Molecular Models Molecular Structure Mood Disorders Mus Neurons Nitric Oxide Nitric Oxide Synthase Outcome Patients Peripheral Pharmaceutical Preparations Pharmacological Treatment Phosphodiesterase Inhibitors Post-Traumatic Stress Disorders Pre-Clinical Model Psychopharmacology RNA Interference Research Signal Pathway Signal Transduction Structure Techniques Testing Therapeutic Validation Viagra analog base chemical synthesis chronic depression computational chemistry depression design drug discovery inhibitor/antagonist interest molecular modeling mouse model neurochemistry neurotensin mimic 2 novel phosphoric diester hydrolase potency testing psychopharmacologic public health relevance research study sildenafil

项目摘要

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.

描述（由申请人提供）：该项目的目的是验证磷酸二酯酶-2（PDE2）作为治疗情绪障碍的药理目标，并发现新颖的选择性抑制剂。 PDE2的抑制通过阻止其水解并产生抗焦虑和抗抑郁药对行为的影响，从而增强了CGMP信号传导。目前，有效和选择性PDE2抑制剂几乎没有。我们的研究利用高级计算分子建模来预测新型PDE2抑制剂的结构。一些已合成用于神经药物和行为评估。为了推进该领域的药物发现，提出了以下特定目标：1）设计和合成PDE2抑制剂，并在体外测试效力和选择性； 2）确定PDE2抑制剂的神经化学和行为作用以及PDE2的RNAi敲低是否模仿PDE2药理抑制后看到的抗焦虑和抗抑郁作用。拟议的实验的完成将导致鉴定急性和慢性治疗后抗焦虑和抗抑郁作用的PDE2抑制作用，合成有希望的化合物的合成以及验证抗焦虑和抗抑郁作用的最佳分子结构。此外，它将提供与情绪障碍相关的PDE2的非药物验证。最终，这将导致用于治疗焦虑症和抑郁症的新药物的发展。此外，成功的交互式分子建模/化学合成/药理学特征模型将为未来涉及其他PDE家族和其他神经心理药理学指示的药物发现工作提供基础。大多数PDE家族在大脑中表达，从CNS药物发现和发育的角度来看，一些家庭似乎具有潜在的兴趣。针对本PDE2项目提出的基本原理，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，尤其是因为PDE抑制已被证明是一种有用的治疗方法（例如，西地那非； sildenafil; I.e.，伟哥）。公共卫生相关性：诸如焦虑和抑郁之类的情绪障碍是长期使人衰弱的疾病。由于许多患者的影响不佳，在某些情况下（例如PTSD）以及可能导致缺乏依从性的副作用，药理学治疗并不是最佳的。需要具有新型作用机理的药物，可能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（PDE2）的抑制剂具有抗焦虑药和抗抑郁药。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。这可能导致鉴定出一种用于治疗情绪障碍的新药物。