High Throughput Behavioral Testing For Novel Antidepressants

新型抗抑郁药的高通量行为测试

• 批准号: 7326301
• 负责人: BARBARA J. CALDARONE
• 金额: $ 25万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326301
• 关键词: Acute; Agonist; Algorithms; Antidepressive Agents; Arts; Behavior; Behavioral; Behavioral Assay; Categories; Chronic; Class; Clinical; Databases; Development; Disease; Drug Kinetics; Exhibits; Fluoxetine; Goals; Grant; Imipramine; Investigational Drugs; Investigational New Drug Application; Lead; Libraries; Major Depressive Disorder; Marketing; Measures; Medical; Mental Depression; Mental disorders; Metabolic; Methodology; Molecular; Molecular Target; Mus; NIH Program Announcements; National Institute of Mental Health; Nature; Nicotinic Receptors; Numbers; Pharmaceutical Preparations; Phase; Probability; Running; Safety; Structure; System; Technology; Testing; Time; Toxic effect; abstracting; base; behavior test; clinical efficacy; data mining; design; driving behavior; drug discovery; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; follow-up; improved; in vivo; inhibitor/antagonist; novel; pre-clinical; response; reuptake; small molecule; small molecule libraries; success; venlafaxine

DESCRIPTION (provided by applicant): CONFIDENTIAL Project Summary/Abstract This application is being submitted in response to an NIMH program announcement for Pharmacological Agents and Drugs for Mental Disorders. The goal of the proposal is to overcome the major hurdles that have impeded the discovery of new and improved antidepressant medications by combining state of the art automated behavioral assay technology with a novel and specialized approach to the discovery of drugs for the treatment of depression. Despite wide use and commercial success, current antidepressants have several deficiencies including poor efficacy and delayed onset of action. Progress in antidepressant drug discovery has been delayed severely by the lack of reliable, high throughput behavioral assays sensitive to the chronic effects of these drugs. We propose to develop SmartCube(r), PsychoGenics' automated, high-throughput behavioral testing system, to screen antidepressants for rapid onset of activity. In Phase I, we will develop a methodology to screen for fast acting antidepressants. To accomplish this, we will first establish the time course and onset of action of the chronic antidepressant signature in SmartCube(r). The time required for the chronic signatures to reach a steady state will be determined for a small set of prototypical antidepressants (fluoxetine, venlafaxine and imipramine). The onset of the chronic signature will be determined for these antidepressants by establishing the earliest time at which the antidepressant signature more closely resembles the chronic rather than acute signature. We will then utilize this information to establish a reference database of chronic antidepressant signatures in SmartCube(r). This reference database will be used to screen novel compounds for fast onset antidepressant activity. Up to 100 compounds that have previously shown activity in our acute antidepressant SmartCube(r) screen will be tested for fast onset activity. The libraries that we have previously screened were comprised of a diverse mix of known and novel, target- specific, target-nonspecific and target-undetermined small molecules. Compounds that show a high probability of showing a chronic antidepressant signature will be considered "preliminary hits". These compounds will be confirmed in tests of chronic antidepressant efficacy that test for onset of action. Compounds that show rapid onset activity in at least one of these tests will be considered "validated hits". In Phase II of the proposal, 3-5 validated hits will be advanced and the metabolic, pharmacokinetic and safety studies required to file an IND for at lead one "optimized lead" will be completed. We believe that this approach will result in the discovery of novel, faster acting antidepressants. CONFIDENTIAL Project Narrative Major depression represents a major unmet medical need, but the number of new medications introduced to the market in recent years has been steadily declining. The traditional molecular target driven approached to drug discovery for antidepressants have had limited success due to the complexity and lack of understanding regarding the molecular basis of the disorder. The behavior-based approach described in this proposal provides an exciting new alternative with the potential to more efficiently identify novel, more efficacious antidepressants with a faster onset of action.

描述（由申请人提供）：机密项目摘要/摘要此申请是为了响应NIMH计划公告的药理药物和精神疾病药物的公告。该提案的目的是克服通过将最先进的自动化行为测定技术与一种新颖而专业的方法相结合，以发现抑郁症治疗的药物，从而阻碍了发现新的和改进的抗抑郁药的主要障碍。尽管使用了广泛的使用和商业上的成功，但目前的抗抑郁药具有多种缺陷，包括功效不佳和作用发作延迟。由于缺乏对这些药物的慢性作用敏感的可靠，高通量行为测定，抗抑郁药发现的进展已严重延迟。我们建议开发SmartCube（R），即心理学的自动化，高通量行为测试系统，以筛选抗抑郁药以快速发作。在第一阶段，我们将开发一种方法来筛选快速作用抗抑郁药。为此，我们将首先建立SmartCube（R）中慢性抗抑郁剂签名的时间过程和动作开始。慢性特征达到稳态所需的时间将用于一组原型抗抑郁药（氟西汀，Venlafaxine和丙咪胺）。通过确定最早的抗抑郁药物更类似于慢性签名而不是急性签名的时间，将确定这些抗抑郁药的慢性特征发作。然后，我们将利用此信息在SmartCube（R）中建立慢性抗抑郁剂特征的参考数据库。该参考数据库将用于筛选新型化合物，以进行快速发作抗抑郁活性。先前在我们的急性抗抑郁药SmartCube（R）屏幕中显示活性的最多100种化合物将进行快速发作活动。我们先前筛选的文库由已知和新颖的，特异性，目标非特异性和目标无确定的小分子组成。显示出慢性抗抑郁药特征的可能性很高的化合物将被视为“初步命中”。这些化合物将在测试作用发作的慢性抗抑郁疗效的测试中得到证实。在其中至少一种测试中显示快速发作活动的化合物将被视为“验证的命中”。在该提案的第二阶段中，将进行3-5个经过验证的命中，并且将完成一项铅的代谢，药代动力学和安全性研究，以便在铅上一个“优化的铅”上提交IND。我们认为，这种方法将导致发现新颖，更快的抗抑郁药。机密项目叙述性重大抑郁症代表了一个主要的未满足医疗需求，但是近年来引入市场的新药物数量一直在稳步下降。由于对该疾病的分子基础的复杂性和缺乏了解，传统的分子靶向抗抑郁药发现的药物发现的方法取得了有限的成功。本提案中描述的基于行为的方法提供了一种令人兴奋的新替代方案，具有更有效地识别新颖，更有效的抗抑郁药的潜力，并以更快的作用开始。