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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：
9116001
负责人：
Thomas P Burris
金额：
$ 62.78万
依托单位：
SAINT LOUIS UNIVERSITY
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116001
关键词：
Address Adult Adverse effects Affect Agonist Animal Disease Models Animals Anti-Anxiety Agents Anxiety Disorders Behavior Behavior Disorders Behavior assessment Behavioral Behavioral Assay Binding Central Nervous System Diseases Circadian Dysregulation Circadian Rhythms Development Disease Dose Drug Kinetics Drug Targeting Evaluation Exposure to Feedback Funding Gene Expression Goals Grant Health Heme Hour Lead Ligands Medical Mental Depression Molecular Mus Nuclear Receptors Orphan Pathway interactions Pattern Pharmaceutical Preparations Pharmacodynamics Pharmacology Physiological Physiology Play Porphyrins Property Publishing Recurrence Regulation Research Rewards Role Sedation procedure Series Source System Testing Therapeutic United States Wakefulness Work base design human disease improved in vivo innovation nervous system disorder novel therapeutics receptor sedative treatment of anxiety disorders

项目摘要

DESCRIPTION (provided by applicant): Dysregulation of the circadian rhythm is associated with several disorders of the nervous system including anxiety 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. Thus, there is a clear unmet medical need for additional classes of therapeutics to treat these disorders. 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-ERBalpha is an NR that has a well-characterized role in the regulation of the circadian rhythm. We have found that REV-ERB agonists that we have designed that has the ability to modulate the circadian rhythm in vivo also display anxiolytic activity in mice. Interestingly, thes compounds display no sedative activity at anxiolytic doses. The REV-ERB agonists we have developed are the first with sufficient in vivo exposure to allow evaluation of its effects in animals; however, their 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 as anxiolytic agents, 2) Evaluate the ability of synthetic REV- ERB ligands for their abiliy 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 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.

描述(申请人提供)：昼夜节律失调与包括焦虑症在内的几种神经系统紊乱有关。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。因此，对治疗这些疾病的额外治疗方法的需求显然还未得到满足。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-ERBalpha是一种在调节昼夜节律中具有良好特征的NR。我们已经发现，我们设计的能够在体内调节昼夜节律的REV-ERB激动剂在小鼠身上也显示出缓解焦虑的活性。有趣的是，这些化合物在抗焦虑剂量下没有表现出镇静活性。我们开发的REV-ERB激动剂是第一个能够在动物体内充分暴露以评估其效果的药物；然而，它们的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说：1)优化用于抗焦虑药物的合成REV-ERB配体的药效学和药代动力学性质，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和有效的REV-ERB激动剂，这些激动剂的特性将允许在动物疾病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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinct roles for REV-ERBα and REV-ERBβ in oxidative capacity and mitochondrial biogenesis in skeletal muscle.

DOI：
10.1371/journal.pone.0196787
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Amador A;Campbell S;Kazantzis M;Lan G;Burris TP;Solt LA
通讯作者：
Solt LA

Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

DOI：
10.1371/journal.pone.0069939
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Vieira E;Marroquí L;Figueroa AL;Merino B;Fernandez-Ruiz R;Nadal A;Burris TP;Gomis R;Quesada I
通讯作者：
Quesada I

Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice.

DOI：
10.1053/j.gastro.2017.12.019
发表时间：
2018-04
期刊：
Gastroenterology
影响因子：
29.4
作者：
Pourcet B;Zecchin M;Ferri L;Beauchamp J;Sitaula S;Billon C;Delhaye S;Vanhoutte J;Mayeuf-Louchart A;Thorel Q;Haas JT;Eeckhoute J;Dombrowicz D;Duhem C;Boulinguiez A;Lancel S;Sebti Y;Burris TP;Staels B;Duez HM
通讯作者：
Duez HM

Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells.