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

• 批准号: 7941951
• 负责人: JAMES M O'DONNELL
• 金额: $ 46.83万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941951
• 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; Mental Depression; 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; 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

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，并发现新的选择性抑制剂。抑制PDE2通过阻断cGMP的水解来增强cGMP信号，并对行为产生抗焦虑和抗抑郁作用。目前，很少有有效的、选择性的PDE2抑制剂。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；一些已被合成用于神经药理学和行为评价。为了进一步推进这一领域的药物发现，我们提出了以下具体目标：1)设计和合成PDE2抑制剂，并进行体外效价和选择性测试；2)确定PDE2抑制剂的神经化学和行为作用，以及RNAi敲低PDE2是否模仿PDE2药物抑制后的抗焦虑和抗抑郁作用。该实验的完成将导致确定PDE2抑制的最佳分子结构，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作用。此外，它将提供PDE2作为与情绪障碍相关的靶标的非药物验证。这最终将导致治疗焦虑症和抑郁症的新药的开发。此外，成功的相互作用分子建模/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，有几个家族似乎有潜在的兴趣。本PDE2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）。