High-Throughput Assay for G-Protein Coupled Receptors in Pain Research

描述(申请人提供)：慢性疼痛是一种衰弱的疾病，在生产力、经济影响和生活质量方面造成很高的社会成本。目前可用的治疗方法在治疗这种疼痛方面取得的成功有限，这表明需要对潜在的机制进行新的洞察(S)。阿片肽通过结合和激活阿片受体来调节痛觉，但由于其多肽特性，即缺乏血脑屏障的穿越和代谢酶的快速失活，其用于疼痛治疗的有效性受到限制。另一方面，小分子生物碱吗啡是一种强大的止痛剂，可以很容易地给药并激活相同的受体。G蛋白偶联受体GPR7是一种与阿片受体序列相似的受体。GPR7被新近发现的神经肽NPW和NPB激活。GPR7被认为调节外周的痛觉。最值得注意的是，虽然在正常情况下，GPR7在脊髓中的表达水平很低；但在患有炎症/免疫介导的神经疾病的患者中，它的表达显著增加。目前还没有可以用来调节GPR7系统的小分子。因此，我们建议使用我们最近开发的强大而简单的GPR7分析系统，由MLSCN的一个中心进行高通量分子文库筛选。通过我们的筛选试验确定的化合物将是有价值的基础研究工具，将极大地促进该项目的长期目标，了解GPR7在慢性疼痛中的参与，它在疼痛传递机制中的作用，以及它与其他疼痛相关通路的相互作用。在已建立动物模型的情况下，对于研究该系统在炎症性神经病变中的作用，小分子化合物将特别有用。公共卫生相关性： 医学上非常需要有效、持久和安全的新化合物来治疗慢性疼痛。拟议研究的总体目标是使用高通量分析方式确定阿片受体相关G蛋白偶联受体GPR7的小分子、选择性激动剂和拮抗剂。通过我们的筛选试验确定的化合物将是有价值的基础研究工具，将极大地促进该项目的长期目标，了解GPR7参与慢性疼痛。

DESCRIPTION (provided by applicant): Chronic pain is a debilitating condition that exerts a high social cost in terms of productivity, economic impact and quality of life. Currently available therapies yield limited success in treating such pain, suggesting the need for new insight into underlying mechanism(s). Opioid peptides modulate pain sensation by binding and activating the opioid receptors, but their usefulness for pain treatment is limited due to their peptidic properties i.e. lack of blood brain barrier crossing and fast inactivation by metabolic enzymes. The small molecule alkaloid morphine, on the other hand, is a powerful analgesic that can be easily administered and activates the same receptors. The G protein coupled receptor, GPR7, is a receptor that shares sequence similarities with opioid receptors. GPR7 is activated by the neuropeptides NPW and NPB which have been recently discovered. GPR7 is thought to regulate pain perception in the periphery. Most notably, while under normal conditions GPR7 is expressed at low levels in the spinal cord; its expression is dramatically increased in patients suffering from inflammatory/immune-mediated neuropathies. Presently there are no small molecules available which could be used to modulate the GPR7 system. We therefore propose to use our recently developed robust and simple assay system for GPR7 in a high-throughput screen of molecular libraries conducted by one of the centers of the MLSCN. Compounds identified through our screening assay will represent valuable basic research tools that will greatly facilitate the long term goal of this project to understand the involvement of GPR7 in chronic pain, its role in the mechanism of pain transmission and its interaction with other pain- related pathways. Small compounds will be in particular useful to study the system with regard to its role in inflammatory neuropathies where established animal models are available. PUBLIC HEALTH RELEVANCE: There is a significant medical need for novel compounds for treating chronic pain that are effective, long lasting and safe. The overall objective of the proposed research is to identify small molecule, selective agonist and antagonists for the opioid receptor related G protein-coupled receptor GPR7 using a high-throughput assay format. Compounds identified through our screening assay will represent valuable basic research tools that will greatly facilitate the long term goal of this project to understand the involvement of GPR7 in chronic pain.