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Opiate Bivalent Ligands:Structure/Function Studies

阿片二价配体：结构/功能研究

基本信息

批准号：
7067639
负责人：
PHILIP S PORTOGHESE
金额：
$ 69.62万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7067639
关键词：
ligands opioid receptor protein structure function

项目摘要

DESCRIPTION (provided by applicant): There is burgeoning evidence that at least some of the pharmacological effects of opioids are mediated via opioid receptors that are organized as dimers or oligomers. Moreover, it is now established that in some cases different types opioid receptors can associate with one another to form heterodimers. The possibility that heterodimers may modulate signal transduction pathways that are not identical to those mediated by monomeric or homodimeric opioid receptors is an intriguing possibility that may have a bearing on tolerance and physical dependence. For these reasons, the broad, long-term objective of this project is to investigate the role of opioid receptor dimerization through a multidisciplinary, coordinated approach. In project 1, pharmacologic tools will be designed and synthesized to identify the presence of mu-delta opioid receptor dimers. The design approach involves the simultaneous occupation of neighboring mu and delta recognition sites in a heterodimer by a single bivalent ligand that contains mu agonist and delta antagonist pharmacophores. Optimization of binding and function will be accomplished by varying the length of the spacer that links the pharmacophores. In project 2, the interaction between mu and delta opioid receptors will be investigated in cultured cells. The activities of the mu receptors will be examined at different levels of expressed delta receptors. The ability of mu-selective opioid agonists to inhibit the production of intracellular CAMP or stimulation of the ERK1/2 activities will be determined when the expressed delta opioid receptors are being activated or inactivated. The ability of mu opioid agonists to elicit cellular adaptive responses such as desensitization or receptor internalization during mu opioid receptor activation or inactivation will be examined. Project 3 involves the molecular simulation of different dimer structures in a variety of dimer interfaces. Each will be built and evaluated according to theoretical scoring functions taken from protein homology and long time-scale molecular dynamics calculations. Bivalent ligands that have been found experimentally to bridge the opioid recognition sites in opioid receptor dimers will be employed as "molecular rulers" to provide information on the distance between binding sites. Chronic testing of the target compounds will be carried out in mice to determine if there are in vivo correlates with the in vitro data obtained in projects 1 and 2.

描述（由申请人提供）：有越来越多的证据表明，至少阿片类药物的某些药理学作用是通过阿片类药物介导的受体被组织为二聚体或寡聚体。而且，现在在某些情况下，不同类型的阿片受体可以与以形成异二聚体。异二聚体可能调节与介导的信号转导途径不同的信号转导途径，单体或同型二聚体阿片受体是一个有趣的可能性，可能与耐受性和身体依赖性有关。由于这些原因，该项目的一个广泛的长期目标是研究阿片类药物的作用受体二聚化通过多学科，协调的方法。在项目1，药理学工具将被设计和合成，以确定 μ-δ阿片受体二聚体的存在。设计方法涉及同时占据邻近的MU和δ识别位点，通过含有μ激动剂和δ的单个二价配体的异二聚体拮抗剂药效团。结合和功能的优化将是通过改变连接药效团的间隔区的长度来实现。在项目2中，μ和δ阿片受体之间的相互作用将是在培养的细胞中研究。mu受体的活性将是在不同水平的表达δ受体进行检查。的能力 μ-选择性阿片激动剂，以抑制细胞内cAMP的产生，或当表达的ERK 1/2活性增加时， δ阿片受体被激活或失活。Mu的能力阿片样物质激动剂以引发细胞适应性反应或μ阿片受体活化过程中的受体内化，将检查灭活情况。项目3涉及的分子模拟在各种二聚体界面中的不同二聚体结构。每一个都将被建造并根据蛋白质的理论评分函数进行评价同源性和长时间尺度分子动力学计算。二价配体实验上发现，它可以连接阿片类识别位点，阿片受体二聚体将被用作“分子统治者”，结合位点之间的距离信息。慢性试验目标化合物将在小鼠中进行，以确定是否存在体内与项目1和2中获得的体外数据相关。