Group II mGluR antagonists and negative modulators in depression

II 组 mGluR 拮抗剂和负调节剂治疗抑郁症

基本信息

项目摘要

DESCRIPTION (provided by applicant): Depression is a serious psychiatric disorder that remains a major public health problem. Approximately 21% of the general population suffers from depression sometime in their lifetime, while the incidence of depression is 30-37% in drug abusers. There has not been development of new antidepressants with novel pharmacological mechanisms of action for several decades. Recent publications and preliminary data reviewed in this application suggest that antagonists or negative allosteric modulators at metabotropic glutamate receptors (mGluR) Group II (mGluR2 and mGluR3) may have antidepressant properties. Thus, mGluR2/3 are novel targets for antidepressant treatment. This new revised R01 application is in response to PAR-07-048 entitled "Drug Discovery for Nervous System Disorders" that encourages the synthesis and "preclinical testing of novel compounds for the prevention and treatment of nervous system disorders". A multidisciplinary research team comprised of chemists (Burnham Institute), in vitro pharmacologists (Vanderbilt University) and behavioral pharmacologists (University of California, San Diego) will focus on the synthesis and testing of new mGluR2/3 orthosteric antagonists and negative allosteric modulators as treatments for depression. Specific Aim 1 will involve the design and synthesis of novel mGluR2/3 orthosteric antagonists and negative allosteric modulators with optimized potency, selectivity, and in vivo activity. Specific Aim 2 will: i) evaluate and characterize the newly synthesized compounds for potency and efficacy at mGluR2, mGluR3, other mGluRs and various other central nervous system molecular targets, and ii) perform absorption, distribution, metabolism and excretion analyses, as well as evaluate blood brain barrier permeation and pharmacokinetics using in vitro and in vivo assays. Once the optimal mGluR2/3 compounds are identified (see Research Plan for criteria used to select compounds), Specific Aim 3 will investigate the effects of these selected compounds in animal models of: i) stress-induced anhedonia involving assessment of elevations in intracranial self-stimulation (ICSS) reward thresholds after chronic social defeat in rats; and ii) antidepressant-like activity in the forced swim test in rats. Anhedonia is defined as diminished interest or pleasure in rewarding stimuli and is considered a core behavioral phenotype of depression. Thus, compounds with demonstrated anti-anhedonic activity in the stress- induced anhedonia model or antidepressant-like activity in the forced swim test and which also exhibit drug-like properties will be considered putative drug candidates for future drug discovery and development efforts. Potential side-effects will be assessed in later years of the project, once drug-like candidates are identified. The proposed multidisciplinary research program is highly significant as it addresses an important public health problem, innovative as it focuses on Group II mGluRs as targets for novel antidepressants, and timely as it is in response to a Program Announcement by NIH. Therefore, this research program has the potential for a significant scientific and medical impact by contributing to the discovery of new medications for depression. PUBLIC HEALTH RELEVANCE: Depression is a serious psychiatric disorder that affects a large percentage of the USA population. The proposed project will synthesize new compounds that will target metabotropic glutamate receptors in the brain and evaluate them for their putative antidepressant activity in animal models of depression. This project is very innovative and promises to have a highly significant overall impact by promoting the discovery of new treatments for this devastating disorder.
描述(申请人提供):抑郁症是一种严重的精神障碍,仍然是一个主要的公共卫生问题。大约21%的普通人群在他们一生中的某个时候患有抑郁症,而在吸毒者中抑郁症的发生率为30%-37%。几十年来,一直没有开发出具有新的药理作用机制的新的抗抑郁药物。最近发表的文献和在本申请中综述的初步数据表明,代谢性谷氨酸受体(MGluR)第二组(mGluR2和mGluR3)的拮抗剂或负变构调节剂可能具有抗抑郁特性。因此,mGluR2/3是抗抑郁药物治疗的新靶点。这一新修订的R01申请是对题为“神经系统疾病的药物发现”的PAR-07-048的响应,该文件鼓励合成和“用于预防和治疗神经系统疾病的新化合物的临床前测试”。一个由化学家(Burnham Institute)、体外药理学家(Vanderbilt University)和行为药理学家(加州大学圣地亚哥分校)组成的多学科研究小组将专注于合成和测试新的mGluR2/3正构拮抗剂和负变构调节剂作为抑郁症的治疗方法。具体目标1将涉及设计和合成具有最佳效力、选择性和体内活性的新型mGluR2/3正构拮抗剂和负变构调节剂。具体目标2将:i)评估和表征新合成的化合物在mGluR2、mGluR3、其他mGluRs和各种其他中枢神经系统分子靶点上的效力和疗效,以及ii)进行吸收、分布、代谢和排泄分析,以及使用体外和体内试验评估血脑屏障通透性和药代动力学。一旦确定了最佳的mGluR2/3化合物(化合物选择标准见研究计划),特定目标3将在以下动物模型中考察这些选定化合物的作用:i)应激性快感贫血,包括评估慢性社会失败后大鼠颅内自我刺激(ICSS)奖赏阈值的升高;ii)大鼠强迫游泳试验中的抗抑郁样活性。快感缺失被定义为对奖励刺激的兴趣或愉悦减弱,被认为是抑郁症的核心行为表型。因此,在应激性快感缺乏症模型中表现出抗快感活性或在强迫游泳试验中表现出抗抑郁药样活性并表现出类药物性质的化合物将被认为是未来药物发现和开发工作的候选药物。一旦确定了类似药物的候选药物,将在该项目的后几年评估潜在的副作用。拟议的多学科研究计划具有非常重要的意义,因为它解决了一个重要的公共卫生问题,它具有创新性,因为它专注于第二组mGluR作为新型抗抑郁药的靶标,而且它是对NIH计划公告的及时回应。因此,这项研究计划有可能对发现治疗抑郁症的新药产生重大的科学和医学影响。 公共卫生相关性:抑郁症是一种严重的精神障碍,影响着美国人口的很大比例。这项拟议的项目将合成新的化合物,这些化合物将针对大脑中的代谢性谷氨酸受体,并在抑郁症动物模型中评估它们可能的抗抑郁活性。该项目非常具有创新性,有望通过促进发现这种破坏性疾病的新疗法来产生非常重大的整体影响。

项目成果

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Nicholas David Cosford其他文献

Nicholas David Cosford的其他文献

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{{ truncateString('Nicholas David Cosford', 18)}}的其他基金

Characterization, optimization, and development of dual mGlu2/3 positive allosteric modulators for opioid use disorder
用于阿片类药物使用障碍的双 mGlu2/3 正变构调节剂的表征、优化和开发
  • 批准号:
    10544440
  • 财政年份:
    2022
  • 资助金额:
    $ 87.81万
  • 项目类别:
Cancer Targets and Drug Discovery
癌症靶点和药物发现
  • 批准号:
    10219171
  • 财政年份:
    2018
  • 资助金额:
    $ 87.81万
  • 项目类别:
Cancer Targets and Drug Discovery
癌症靶点和药物发现
  • 批准号:
    10443758
  • 财政年份:
    2018
  • 资助金额:
    $ 87.81万
  • 项目类别:
Lead optimization of Novel mGlu2 Negative Allosteric Modulators
新型 mGlu2 负变构调节剂的先导化合物优化
  • 批准号:
    9251915
  • 财政年份:
    2016
  • 资助金额:
    $ 87.81万
  • 项目类别:
Lead optimization of Novel mGlu2 Negative Allosteric Modulators
新型 mGlu2 负变构调节剂的先导化合物优化
  • 批准号:
    9029750
  • 财政年份:
    2016
  • 资助金额:
    $ 87.81万
  • 项目类别:
Lead Optimization of Novel Inhibitors of the Thioesterase Domain of FASN
FASN 硫酯酶结构域新型抑制剂的先导化合物优化
  • 批准号:
    9090093
  • 财政年份:
    2014
  • 资助金额:
    $ 87.81万
  • 项目类别:
Lead Optimization of Novel Inhibitors of the Thioesterase Domain of FASN
FASN 硫酯酶结构域新型抑制剂的先导化合物优化
  • 批准号:
    8768420
  • 财政年份:
    2014
  • 资助金额:
    $ 87.81万
  • 项目类别:
Lead Optimization of Novel Inhibitors of Tissue Non-specific Alkaline Phosphatase
新型组织非特异性碱性磷酸酶抑制剂的先导化合物优化
  • 批准号:
    8579764
  • 财政年份:
    2013
  • 资助金额:
    $ 87.81万
  • 项目类别:
Lead Optimization of Novel Inhibitors of Tissue Non-specific Alkaline Phosphatase
新型组织非特异性碱性磷酸酶抑制剂的先导化合物优化
  • 批准号:
    8727436
  • 财政年份:
    2013
  • 资助金额:
    $ 87.81万
  • 项目类别:
Identifying Chemical Modulators of CRF-Binding Protein and CRF Receptor Complexes
鉴定 CRF 结合蛋白和 CRF 受体复合物的化学调节剂
  • 批准号:
    8514550
  • 财政年份:
    2010
  • 资助金额:
    $ 87.81万
  • 项目类别:

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Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    8077875
  • 财政年份:
    2010
  • 资助金额:
    $ 87.81万
  • 项目类别:
Real-time Disambiguation of Abbreviations in Clinical Notes
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  • 批准号:
    7866149
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Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    8589822
  • 财政年份:
    2010
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    $ 87.81万
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Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
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    8305149
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