REV-ERB ligands for treatment of anxiety disorders

用于治疗焦虑症的 REV-ERB 配体

• 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
• 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

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（由申请人提供）：昼夜节律失调与多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。对于治疗这些疾病的其他类别的疗法，显然存在未满足的医疗需求。焦虑症是一种严重的疾病，影响着美国约 4000 万成年人。苯二氮卓类药物是最常用的抗焦虑药物，但其使用会带来显着的副作用，包括镇静、耐受性和滥用的可能性。现在有许多抗焦虑药物可供使用，但这些药物也不是最佳的。这项拟议的研究基于我们最近的发现，即我们可以使用特定核受体 (NR) REV-ERB 的合成配体调节体内昼夜节律。 REV-ERBa 是一种在昼夜节律调节中具有明确作用的 NR。我们发现我们设计的 REV-ERB 激动剂 SR9011 能够在体内调节昼夜节律，并且在小鼠中也显示出抗焦虑活性。有趣的是，SR9011 在具有抗焦虑活性的剂量下没有表现出镇静活性。 SR9011是第一个体内暴露量足以评估其在动物中的作用的REV-ERB配体；然而，其药效学和药代动力学特性远非最佳。我们假设优化的合成 REV-ERB 配体将可用于治疗焦虑症。我们将通过关注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 配体的药效和药代动力学特性，2）评估合成 REV-ERB 配体调节昼夜节律的能力体内行为/生理学，3) 优化 REV-ERB 激动剂体内的抗焦虑活性，并表征其镇静活性和滥用潜力。我们现在已经开发了一系列非常有效的 REV-ERB 激动剂和拮抗剂，它们具有可以在疾病动物模型中评估这些化合物的特性。因此，我们提出的研究具有高度创新性，并且有可能产生巨大影响，因为这项工作可能会产生用于治疗焦虑症以及其他行为障碍的新药物。 公共健康相关性：我们发现核受体 REV-ERB 受配体调节，并已表征了该受体的合成激动剂和拮抗剂。该受体是昼夜节律的关键调节剂，昼夜节律失调与包括焦虑症在内的多种神经系统疾病有关。我们发现 REV-ERB 激动剂表现出抗焦虑活性，本提案的目标是开发具有优化药效和药代动力学特性的 REV-ERB 激动剂，用作抗焦虑剂。