Ligands that target opioid-chemokine and opioid-mGlu5 heteromers

靶向阿片类趋化因子和阿片类 mGlu5 异聚体的配体

基本信息

  • 批准号:
    8653945
  • 负责人:
  • 金额:
    $ 52.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-01 至 2016-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Opioid analgesics remain the drug of choice for management of acute and chronic pain. However, for treatment of pain in the presence of inflammation, their use is limited because inflammation reduces the efficacy of opioids. This is due primarily to chemokines whose release in the inflammatory state is responsible for promoting increased levels of glutamate that leads to a lowering of the pain threshold. In this regard, the use of morphine, either with a chemokine receptor antagonist or a metabotropic glutamate-5 receptor (mGluR5) antagonist, are known to increase the efficacy of morphine and prevent the establishment of side effects such as tolerance, dependence, constipation, etc., under inflammatory conditions. Given the coexistence of opioid, chemokine, and mGluR5 receptors in glia and neurons, together with reports that indicate coexpressed opioid/chemokine and opioid/mGluR5 receptors in cultured cells associate as heteromers, there is a reasonable possibility that similar association of these receptors exists in vivo. We therefore propose to synthesize and biologically evaluate ligands that selectively target putative heteromers of opioid-chemokine and opioid-mGlu5 receptors for use as pharmacological tools in an effort to bridge the divide between cultured cells and in vivo pharmacology. Our approach involves the attachment of a mu opioid agonist pharmacophore to either a chemokine (CCR5, or CXCR4) antagonist (series 1, 2) or mGluR5 antagonist (series 3) pharmacophore via a spacer. Each member of the series will contain homologous spacers in order to assess the optimal bridging to each of the heteromers. Monovalent ligands (series 4-7) containing the above pharmacophores also will be synthesized as controls for this study. Functional studies of these series will be conducted in cultured cells that contain heteromers (MOPR-CCR5, MOPR-CXCR4, and MOPR-mGluR5) or the corresponding homomers. Immunofluorescence studies on these cells will be conducted in order to study trafficking of receptors that are activated by heteromer-selective bivalent ligands. Bivalent ligands that are potent, selective, and whose characteristics are consistent with bridging of opioid-chemokine and opioid-mGluR5 heteromers devoid of tolerance will be tested in mice. In the long term, the approach of activating opioid receptors while simultaneously antagonizing chemokine or mGluR5 receptors could lead to the development of improved analgesics devoid of the classical side effects of morphine.
描述(由申请人提供):阿片类镇痛药仍然是治疗急性和慢性疼痛的首选药物。然而,对于存在炎症的疼痛的治疗,它们的使用是有限的,因为炎症降低了阿片类药物的疗效。这主要是由于趋化因子,其在炎症状态下的释放负责促进谷氨酸水平的增加,从而导致疼痛阈值的降低。在这方面,已知吗啡与趋化因子受体拮抗剂或代谢型谷氨酸-5受体(mGluR 5)拮抗剂一起使用可增加吗啡的功效并防止副作用如耐受性、依赖性、便秘等的形成,在炎症条件下。考虑到阿片样物质、趋化因子和mGluR 5受体在神经胶质细胞和神经元中的共存,以及表明在培养的细胞中共表达的阿片样物质/趋化因子和阿片样物质/mGluR 5受体以异聚体形式缔合的报道,存在这些受体在体内存在类似缔合的合理可能性。因此,我们建议合成和生物学评价配体,选择性靶向假定的异源聚体的阿片类趋化因子和阿片类mGlu 5受体作为药理学工具,努力弥合培养细胞和体内药理学之间的鸿沟。我们的方法涉及通过间隔区将μ阿片激动剂药效团连接到趋化因子(CCR 5或CXCR 4)拮抗剂(系列1,2)或mGluR 5拮抗剂(系列3)药效团。该系列的每个成员将含有同源间隔区,以评估与每个异聚体的最佳桥接。还将合成含有上述药效团的单价配体(系列4-7)作为本研究的对照。这些系列的功能研究将在含有异聚体(MOPR-CCR 5、MOPR-CXCR 4和MOPR-mGluR 5)或相应同聚体的培养细胞中进行。将对这些细胞进行免疫荧光研究,以研究被异源选择性二价配体激活的受体的运输。将在小鼠中测试有效的、选择性的并且其特征与阿片样物质-趋化因子和缺乏耐受性的阿片样物质-mGluR 5异聚体的桥接一致的二价配体。从长远来看,激活阿片受体同时拮抗趋化因子或mGluR 5受体的方法可能会导致开发出没有吗啡经典副作用的改进镇痛药。

项目成果

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PHILIP S PORTOGHESE其他文献

PHILIP S PORTOGHESE的其他文献

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{{ truncateString('PHILIP S PORTOGHESE', 18)}}的其他基金

Ligands that target opioid-chemokine and opioid-mGlu5 heteromers
靶向阿片类趋化因子和阿片类 mGlu5 异聚体的配体
  • 批准号:
    8293118
  • 财政年份:
    2011
  • 资助金额:
    $ 52.89万
  • 项目类别:
Ligands that target opioid-chemokine and opioid-mGlu5 heteromers
靶向阿片类趋化因子和阿片类 mGlu5 异聚体的配体
  • 批准号:
    8182577
  • 财政年份:
    2011
  • 资助金额:
    $ 52.89万
  • 项目类别:
Ligands that target opioid-chemokine and opioid-mGlu5 heteromers
靶向阿片类趋化因子和阿片类 mGlu5 异聚体的配体
  • 批准号:
    8459585
  • 财政年份:
    2011
  • 资助金额:
    $ 52.89万
  • 项目类别:
Opiate Bivalent Ligands:Structure/Function Studies
阿片二价配体:结构/功能研究
  • 批准号:
    6751686
  • 财政年份:
    2002
  • 资助金额:
    $ 52.89万
  • 项目类别:
Opiate Bivalent Ligands:Structure/Function Studies
阿片二价配体:结构/功能研究
  • 批准号:
    6460397
  • 财政年份:
    2002
  • 资助金额:
    $ 52.89万
  • 项目类别:
Opiate Bivalent Ligands:Structure/Function Studies
阿片二价配体:结构/功能研究
  • 批准号:
    6623030
  • 财政年份:
    2002
  • 资助金额:
    $ 52.89万
  • 项目类别:
Opiate Bivalent Ligands:Structure/Function Studies
阿片二价配体:结构/功能研究
  • 批准号:
    7067639
  • 财政年份:
    2002
  • 资助金额:
    $ 52.89万
  • 项目类别:
Opiate Bivalent Ligands:Structure/Function Studies
阿片二价配体:结构/功能研究
  • 批准号:
    6881610
  • 财政年份:
    2002
  • 资助金额:
    $ 52.89万
  • 项目类别:
SELECTIVE FLUORESCENT PROBES FOR OPIOID RECEPTOR TYPES
用于阿片受体类型的选择性荧光探针
  • 批准号:
    6237944
  • 财政年份:
    1997
  • 资助金额:
    $ 52.89万
  • 项目类别:
SELECTIVE FLUORESCENT PROBES FOR OPIOID RECEPTOR TYPES
用于阿片受体类型的选择性荧光探针
  • 批准号:
    2120949
  • 财政年份:
    1993
  • 资助金额:
    $ 52.89万
  • 项目类别:

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