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REV-ERB ligands for treatment of anxiety disorders

用于治疗焦虑症的 REV-ERB 配体

基本信息

批准号：
8237792
负责人：
Thomas P Burris
金额：
$ 88.35万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237792
关键词：
Address Adult Adverse effects Affect Agonist Animal Disease Models Animal Model Animals Anti-Anxiety Agents Anxiety Anxiety Disorders Behavior Behavior Disorders Binding Central Nervous System Diseases Circadian Dysregulation Circadian Rhythms Development Disease Dose Drug Delivery Systems Drug Kinetics Evaluation Exhibits Exposure to Feedback Gene Expression Goals Heme Hour Lead Ligands Medical Mental Depression Molecular Molecular Target Mus Nuclear Receptors Orphan Pathway interactions Pattern Pharmaceutical Preparations Pharmacodynamics Physiological Physiology Play Porphyrins Property Recurrence Regulation Reporting Research Role Schizophrenia Sedation procedure Series Sleep Disorders Source System Testing Therapeutic United States Work base design human disease improved in vivo innovation nervous system disorder novel receptor scaffold sedative tool

项目摘要

DESCRIPTION (provided by applicant): Dysregulation of the circadian rhythm is associated with several disorders of the nervous system including depression, anxiety, schizophrenia and sleep disorders. There is a clear unmet medical need for additional classes of therapeutics to treat these disorders. Anxiety disorders are a serious medical illness affecting approximately 40 million adults in the United States. Benzodiazepenes are the most commonly utilized anxiolytic drugs, but their use is associated with significant side effects including sedation, tolerance and potential for abuse. There are a number of anxiolytic drugs that are now available, but these also are less than optimal. This proposed research is based on our recent discovery that we can modulate the circadian rhythm in vivo with synthetic ligands for a particular nuclear receptor (NR), REV-ERB. REV-ERBa is an NR that has a well characterized role in the regulation of the circadian rhythm. We have found that a REV-ERB agonist that we have designed, SR9011,that has the ability to modulate the circadian rhythm in vivo also displays anxiolytic activity in mice. Interestingly, SR9011 displayed no sedative activity at a dose that exhibited anxiolytic activity. SR9011 is the first REV-ERB ligand with sufficient in vivo exposure to allow evaluation of its effects in animals; however, its pharmacodynamic and pharmcokinetic properties are far from optimal. We hypothesize that optimized synthetic REV-ERB ligands will have utility in treatment of anxiety disorders. We will address this hypothesis by focusing on the following specific aims: 1) Optimize the pharmacodynamic and pharmacokinetic properties of synthetic REV-ERB ligands for use in the CNS, 2) Evaluate the ability of synthetic REV-ERB ligands for their ability to modulate circadian behavior/physiology in vivo, 3) Optimize the anxiolytic activity of REV-ERB agonists in vivo and characterize their sedative activity and potential for abuse. We have now developed a series of very potent and efficacious REV-ERB agonists as well as antagonists that have properties that will allow for evaluation of these compounds in animal models of disease. Thus, our proposed research is highly innovative and has the potential to have high impact since this work may lead to novel drugs for the treatment of anxiety disorders as well as other behavioral disorders. PUBLIC HEALTH RELEVANCE: We discovered that the nuclear receptor REV-ERB is ligand regulated and have characterized both synthetic agonists and antagonists of this receptor. This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including anxiety disorders. We have discovered that REV-ERB agonists display anxiolytic activity and the goal of this proposal is to develop REV-ERB agonists with optimized pharmacodynamic and pharmacokinetic properties for use as anxiolytic agents.

描述(申请人提供)：昼夜节律失调与几种神经系统疾病有关，包括抑郁、焦虑、精神分裂症和睡眠障碍。显然，治疗这些疾病需要更多类别的治疗药物，这一需求尚未得到满足。焦虑症是一种严重的疾病，在美国大约有4000万成年人受到影响。苯并二氮烯是最常用的抗焦虑药物，但它们的使用与显著的副作用有关，包括镇静、耐受性和滥用的可能性。现在有许多抗焦虑的药物，但这些药物也不是最理想的。这项拟议的研究是基于我们最近的发现，即我们可以在体内使用针对特定核受体(NR)的合成配体REV-ERB来调节昼夜节律。Rev-Erba是一种在调节昼夜节律中具有独特作用的NR。我们已经发现，我们设计的REV-ERB激动剂SR9011，能够在体内调节昼夜节律，在小鼠身上也显示出缓解焦虑的活性。有趣的是，SR9011在表现出抗焦虑活性的剂量下没有表现出镇静活性。SR9011是第一个REV-ERB配体，具有足够的体内暴露，使其能够在动物身上评估其效果；然而，其药效学和药代动力学性质远未达到最佳。我们推测，优化的合成REV-ERB配体将在焦虑症的治疗中发挥作用。我们将通过以下具体目标来解决这一假设：1)优化用于中枢神经系统的合成REV-ERB配体的药效学和药代动力学特性，2)评估合成REV-ERB配体在体内调节昼夜行为/生理的能力，3)优化REV-ERB激动剂在体内的抗焦虑活性，并表征其镇静活性和滥用的可能性。我们现在已经开发了一系列非常有效的REV-ERB激动剂以及拮抗剂，它们的性质将允许在疾病的动物模型中评估这些化合物。因此，我们提出的研究具有很高的创新性，并有可能产生很大的影响，因为这项工作可能会导致治疗焦虑症和其他行为障碍的新药。公共卫生相关性：我们发现核受体Rev-ERB是受配体调节的，并且已经表征了该受体的合成激动剂和拮抗剂。这种受体是昼夜节律的关键调节器，昼夜节律的失调与包括焦虑症在内的几种神经系统紊乱有关。我们发现REV-ERB激动剂具有抗焦虑活性，本研究的目标是开发具有最佳药效学和药代动力学特性的REV-ERB激动剂，用于抗焦虑药物。