Kappa opioid antagonists: synthesis, potency, selectivity, and time-course

Kappa 阿片拮抗剂:合成、效力、选择性和时程

基本信息

  • 批准号:
    8143394
  • 负责人:
  • 金额:
    $ 7.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-09-30 至 2013-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): New and improved treatments with novel mechanisms of action are needed for drug addiction, mood and anxiety disorders. The kappa opioid receptor (KOR) has recently been validated as a highly promising target for this purpose. Selective KOR antagonists may prevent stress-induced relapse, limit drug use, and provide antidepressant and anxiolytic effects. While available selective KOR antagonists (e.g., norBNI, JDTic) showed efficacy in rodent models used to study drug addiction, mood and anxiety disorders, they do not possess optimal properties to enter clinical studies. Specifically, a single dose in rodents or non-human primates induces long lasting (several weeks) in vivo KOR blockade after a slow onset of action (~24 h). Improved selective KOR antagonists are needed to determine if this class of compounds is effective in clinical settings. Recent efforts focusing on the design of drugs targeting the mu opioid receptor (MOR) have led to the identification of a small number of KOR antagonists with some degree of selectivity for KOR over MOR. These biaryl/diaryl ether containing compounds are structurally different from current KOR antagonists and have mostly been characterized in vitro. Preliminary observations indicate that these agents induce rapid KOR blockade (within 1 h post-administration). This distinguishes this class of compounds from all currently studied, prototypical KOR antagonists and strongly suggests that these compounds will possess a different, more drug-like, time course of KOR blockade. First, we propose to synthesize eleven biaryl/diaryl ether analogues: four known and seven newly designed agents. Binding and functional assays will then be used to assess in vitro KOR antagonist potency and selectivity for KOR over other opioid receptor subtypes. The standard KOR antagonists norBNI and JDTic will be tested under the same conditions to provide reference data. Finally, the two most potent and selective biaryl/diaryl ether agents and the standard KOR antagonist JDTic will be evaluated in the rat intracranial self stimulation test to provide information about in vivo potency and time course of KOR blockade. This assay is sensitive to the function of brain reward systems, making it specifically relevant to identifying agents that might have effects in drug addiction and mood disorders. The identification of short-acting KOR antagonists would have important implications. These agents could be used (1) as lead compounds for further chemical modification, if receptor selectivity needs to be increased, (2) in preclinical studies in which long-lasting KOR blockade is a limitation, and (3) for clinical studies in patients with drug addiction, depression and/or anxiety disorders. This work is of particular importance because it could lead to the development of clinically useful compounds with entirely new mechanisms of action for the treatment of drug addiction, mood and anxiety disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies suggest that selective kappa opioid receptor antagonists have great potential to alleviate symptoms of drug addiction, mood and anxiety disorders. Using a combination of synthesis, in vitro, and in vivo evaluation, the proposed studies seek to identify a class of agents with optimal kappa opioid receptor antagonist properties for use in clinical trials. This work is of particular importance because it could lead to the development of clinically useful compounds with entirely new mechanisms of action, which might help those who respond poorly or inadequately to currently available treatments.
描述(由申请人提供):需要新的和改进的治疗药物成瘾、情绪和焦虑症的新的作用机制。Kappa阿片受体(KOR)最近被证实是一个非常有希望的靶标。选择性的KOR拮抗剂可以防止应激引起的复发,限制药物的使用,并提供抗抑郁和缓解焦虑的作用。尽管现有的选择性KOR拮抗剂(如NorBNI、JDTic)在用于研究药物成瘾、情绪和焦虑症的啮齿动物模型中显示了有效性,但它们并不具备进入临床研究的最佳特性。具体地说,在啮齿动物或非人类灵长类动物中,单次给药可在缓慢开始作用(~24小时)后,在体内诱导长时间(数周)的KOR阻断。需要改进的选择性KOR拮抗剂来确定这类化合物在临床环境中是否有效。最近集中于针对MU阿片受体(MOR)的药物设计的努力导致了对KOR比MOR具有一定程度选择性的少量KOR拮抗剂的确定。这些含有联芳基/二芳基醚的化合物在结构上不同于现有的KOR拮抗剂,并且大多是在体外表征的。初步观察表明,这些药物可引起KOR的快速阻断(在给药后1小时内)。这类化合物有别于目前研究的所有典型的KOR拮抗剂,并强烈表明这些化合物将具有不同的、更像药物的KOR封锁时间过程。首先,我们建议合成11个联芳基/二芳基醚类似物:4个已知试剂和7个新设计的试剂。然后将使用结合和功能分析来评估KOR拮抗剂的体外效力和对其他阿片受体亚型的KOR的选择性。KOR标准拮抗剂NorBNI和JDTic将在相同条件下进行测试,以提供参考数据。最后,两种最有效和选择性最高的联芳基/二芳基醚药物和标准的KOR拮抗剂JDTic将在大鼠颅内自我刺激试验中进行评估,以提供关于KOR阻断的体内效力和时间进程的信息。这项测试对大脑奖励系统的功能很敏感,使其与识别可能对药物成瘾和情绪障碍产生影响的药物特别相关。确定KOR短效拮抗剂将具有重要意义。这些药物可用作(1)进一步化学修饰的先导化合物(如果受体选择性需要增加),(2)在以长期KOR阻断为限制的临床前研究中,以及(3)在药物成瘾、抑郁和/或焦虑症患者的临床研究中。这项工作具有特别重要的意义,因为它可能导致临床上有用的化合物的开发,这些化合物具有治疗药物成瘾、情绪和焦虑障碍的全新作用机制。 公共卫生相关性:临床前研究表明,选择性kappa阿片受体拮抗剂在缓解药物成瘾、情绪和焦虑症方面具有巨大潜力。利用体外合成和体内评估相结合的方法,拟议的研究试图确定一类具有最佳kappa阿片受体拮抗剂性能的药物,用于临床试验。这项工作特别重要,因为它可能导致具有全新作用机制的临床有用化合物的开发,这可能会帮助那些对现有治疗反应不佳或不充分的人。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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William A. Carlezon其他文献

Dérivés de salvinorine et leurs utilisations
萨尔维诺林及其用途的衍生品
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    C. Béguin;Justin S. Potuzak;T. Munro;Kath Duncan;William A. Carlezon;Bruce M. Cohen;Lee
  • 通讯作者:
    Lee
Super glue: emerging roles for non-neuronal brain cells in mental health
强力胶:非神经元脑细胞在心理健康中的新兴作用
  • DOI:
    10.1038/s41386-021-01115-1
  • 发表时间:
    2021-07-26
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    William A. Carlezon;Galen Missig
  • 通讯作者:
    Galen Missig
Inflammatory pain in mice induces light cycle-dependent effects on sleep architecture
小鼠的炎症性疼痛诱导对睡眠结构的光周期依赖性效应
  • DOI:
    10.1038/s41386-025-02152-w
  • 发表时间:
    2025-06-22
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Dominika J. Burek;Khairunisa Mohamad Ibrahim;Andrew G. Hall;Ashish Sharma;Jessica A. Cucinello-Ragland;Erik S. Musiek;Jose A. Morón;William A. Carlezon
  • 通讯作者:
    William A. Carlezon
Ascent of the kappa-opioid receptor in psychopharmacology
  • DOI:
    10.1007/s00213-010-1849-0
  • 发表时间:
    2010-04-17
  • 期刊:
  • 影响因子:
    3.300
  • 作者:
    William A. Carlezon;Klaus A. Miczek
  • 通讯作者:
    Klaus A. Miczek
Sleep as a translationally-relevant endpoint in studies of autism spectrum disorder (ASD)
睡眠作为自闭症谱系障碍(ASD)研究中与翻译相关的终点
  • DOI:
    10.1038/s41386-019-0409-5
  • 发表时间:
    2019-05-06
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Galen Missig;Christopher J. McDougle;William A. Carlezon
  • 通讯作者:
    William A. Carlezon

William A. Carlezon的其他文献

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{{ truncateString('William A. Carlezon', 18)}}的其他基金

Training to Enhance Alignment of Psychiatry and Neuroscience
加强精神病学和神经科学协调的培训
  • 批准号:
    10591484
  • 财政年份:
    2021
  • 资助金额:
    $ 7.66万
  • 项目类别:
Roles of nuleus accumbens CREB and Kappa function in depression
伏隔核 CREB ​​和 Kappa 功能在抑郁症中的作用
  • 批准号:
    10687178
  • 财政年份:
    2021
  • 资助金额:
    $ 7.66万
  • 项目类别:
Roles of nuleus accumbens CREB and Kappa function in depression
伏隔核 CREB ​​和 Kappa 功能在抑郁症中的作用
  • 批准号:
    10490460
  • 财政年份:
    2021
  • 资助金额:
    $ 7.66万
  • 项目类别:
Training to Enhance Alignment of Psychiatry and Neuroscience
加强精神病学和神经科学协调的培训
  • 批准号:
    10170928
  • 财政年份:
    2021
  • 资助金额:
    $ 7.66万
  • 项目类别:
Roles of nuleus accumbens CREB and Kappa function in depression
伏隔核 CREB ​​和 Kappa 功能在抑郁症中的作用
  • 批准号:
    10380269
  • 财政年份:
    2021
  • 资助金额:
    $ 7.66万
  • 项目类别:
Training to Enhance Alignment of Psychiatry and Neuroscience
加强精神病学和神经科学协调的培训
  • 批准号:
    10390406
  • 财政年份:
    2021
  • 资助金额:
    $ 7.66万
  • 项目类别:
SPARED Center
幸免中心
  • 批准号:
    10116476
  • 财政年份:
    2019
  • 资助金额:
    $ 7.66万
  • 项目类别:
Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (SPARED) at McLean Hospital
Silvio O. Conte 应激肽高级研究、教育中心,
  • 批准号:
    10579991
  • 财政年份:
    2019
  • 资助金额:
    $ 7.66万
  • 项目类别:
Roles of CRF-PACAP systems in sleep in mice (Carlezon)
CRF-PACAP 系统在小鼠睡眠中的作用 (Carlezon)
  • 批准号:
    10356106
  • 财政年份:
    2019
  • 资助金额:
    $ 7.66万
  • 项目类别:
Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (SPARED) at McLean Hospital
Silvio O. Conte 应激肽高级研究、教育中心,
  • 批准号:
    10116474
  • 财政年份:
    2019
  • 资助金额:
    $ 7.66万
  • 项目类别:

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A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
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    2023
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