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）：该项目的目标是验证磷酸二酯酶-2 (PDE2) 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。抑制 PDE2 可通过阻断其水解来增强 cGMP 信号传导，并对行为产生抗焦虑和抗抑郁作用。目前，有效且选择性的 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；有些已被合成用于神经药理学和行为评估。为了推进该领域的药物发现，提出以下具体目标：1）设计和合成PDE2抑制剂并测试体外效力和选择性； 2) 确定 PDE2 抑制剂的神经化学和行为效应，以及 PDE2 的 RNAi 敲低是否模拟 PDE2 药理抑制后的抗焦虑和抗抑郁作用。完成所提出的实验将导致确定 PDE2 抑制的最佳分子结构、合成有前景的化合物以及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 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，成功的交互式分子建模/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 CNS 药物发现和开发的角度来看，其中一些家族似乎具有潜在的意义。为当前 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，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，因为许多个体患者效果不佳，对某些病症（如创伤后应激障碍）无效，而且副作用可能导致依从性不足。需要具有新的作用机制、可以表现出更大功效和更少副作用的药物。我们发现磷酸二酯酶 2 (PDE2) 抑制剂有望作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 PDE2 抑制剂的神经化学和行为效应。这可能会导致鉴定出一类用于治疗情绪障碍的新药物。