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
• 负责人: PHILIP S PORTOGHESE
• 金额: $ 50.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8459585
• 关键词: Absence of pain sensation; Acute Pain; Address; Adverse effects; Agonist; Analgesics; Binding; Biological; Biological Assay; CCR5 gene; CXCR4 Receptors; CXCR4 gene; Calcium; Cells; Characteristics; Chemokine (C-C Motif) Receptor 5; Chronic; Constipation; Controlled Study; Cultured Cells; Dependence; Development; Evaluation; Family; GRM5 gene; Glutamates; Goals; Immunofluorescence Immunologic; Inflammation; Inflammatory; Lead; Length; Ligands; Link; Mediating; Morphine; Mus; Neuraxis; Neuroglia; Neurons; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pain Threshold; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Reporting; Series; Testing; base; chemokine; chemokine receptor; chronic pain; improved; in vivo; member; metabotropic glutamate receptor 5; mu opioid receptors; novel; pharmacophore; preference; prevent; receptor; tool; trafficking

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治疗，它们的使用受到限制，因为炎症会降低阿片类药物的功效。这主要是由于在炎症状态下释放的趋化因子负责促进谷氨酸水平的增加，从而降低疼痛阈值。在这方面，已知使用吗啡，无论是趋化因子受体拮抗剂还是代谢性谷氨酸-5受体（mGluR5）拮抗剂，都可以增加吗啡的疗效，并防止在炎症条件下产生耐受性、依赖性、便秘等副作用。鉴于阿片、趋化因子和mGluR5受体在胶质细胞和神经元中共存，并且有报道表明，在培养细胞中，共表达的阿片/趋化因子和阿片/mGluR5受体作为异聚体存在，因此这些受体在体内存在类似关联的可能性是合理的。因此，我们建议合成并对选择性靶向阿片趋化因子和阿片mglu5受体异构体的配体进行生物学评估，以作为药理学工具，努力弥合培养细胞和体内药理学之间的分歧。我们的方法是通过间隔剂将mu阿片激动剂药效团附着在趋化因子（CCR5或CXCR4）拮抗剂（系列1、2）或mGluR5拮抗剂（系列3）药效团上。该系列的每个成员将包含同源间隔，以评估最佳桥接到每个异构体。含有上述药效团的单价配体（系列4-7）也将被合成作为本研究的对照。这些系列的功能研究将在含有异聚体（MOPR-CCR5、MOPR-CXCR4和MOPR-mGluR5）或相应同质体的培养细胞中进行。将对这些细胞进行免疫荧光研究，以研究被异聚选择性二价配体激活的受体的运输。二价配体是有效的、选择性的，其特征与阿片趋化因子和阿片- mglur5异构体的桥接一致，缺乏耐受性，将在小鼠中进行测试。从长远来看，在激活阿片受体的同时拮抗趋化因子或mGluR5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。