Structure and Function of CB2 Receptor

CB2受体的结构和功能

• 批准号: 10245042
• 负责人: Laura M. Bohn
• 金额: $ 76.36万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245042
• 关键词: Affinity; Agonist; Amino Acids; Binding; Binding Sites; Biological; Biological Assay; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Chemicals; Collaborations; Complex; Coupled; Crystallization; Development; Drug Design; Enzymes; Evaluation; Event; Exhibits; Future; G-Protein-Coupled Receptors; Generations; Goals; Human; Imidazole; Inflammation; Laboratories; Ligand Binding; Ligand Binding Domain; Ligands; Lipid Binding; Lipids; Metabolic; Naphthyridines; Nature; Pain; Pathway interactions; Pharmacology; Physiological Processes; Positioning Attribute; Property; Proteins; Pyrazoles; Quinolones; Research Proposals; Role; Signal Transduction; Structure; Therapeutic; Work; addiction; analog; anandamide; base; design; drug candidate; endogenous cannabinoid system; experience; improved; insight; interest; molecular recognition; nervous system disorder; novel; programs; prototype; radioligand; receptor; receptor binding; response; side effect; success; therapeutic development; three dimensional structure; tool

PROJECT SUMMARY The central focus of this Multi-PI R01 research proposal is the structure-function characterization of the human cannabinoid receptor 2 (CB2), a key protein component of the endocannabinoid system. We aim to develop a fundamental understanding of the structural basis of CB2 function, with the ultimate translational goal of establishing a robust structure-based drug design (SBDD) program. The ECS is a complex network of lipid ligands, receptors, and metabolic enzymes involved in a wide range of important physiological processes. There have been important implications that targeting CB2 may be useful as a means for treating inflammation, pain, neurological disorders and addiction. As with other G protein-coupled receptors (GPCRs), CB2 can exhibit preferential signaling events in response to different ligands. This functional selectivity offers the opportunity to refine therapeutic approaches, to improve beneficial properties, and reduce side effect liability. The study will provide the structural basis for the design and development of pharmacologically distinct CB2-selective compounds as useful biological probes and/or leads for the future development of therapeutics. To enhance our effort in obtaining high quality crystal structures, we shall use carefully designed ligands with high affinities and selectivities for CB2, and which are also capable of tight attachment at or near the receptor’s binding domain(s) coupled with their abilities to form crystallizable ligand-receptor complexes. The study has three specific aims: (1) Design and synthesize novel irreversible ligands representing key classes of CB2 selective compounds with distinct functional profiles. (2) Extensive characterization of the newly synthesized ligands in order to identify compounds with pharmacologically diverse profiles, including the partial agonists, inverse agonists, neutral antagonists and allosteric modulators. The crystallization candidates and their chemical derivatives will also be characterized for their reversible binding nature using functional assays. (3) Develop a clear understanding of CB2 ligand binding sites by determining the 3-D structures of the several receptor-ligand complexes. Towards these goals, several crystal structures will be solved to better understand molecular recognition, signaling, and to assist in the design of novel compounds that could then serve as prototypes for later generation leads and drug candidates.

项目概要 这项 Multi-PI R01 研究计划的核心重点是人类的结构功能表征 大麻素受体 2 (CB2)，内源性大麻素系统的关键蛋白质成分。我们的目标是发展 对 CB2 功能的结构基础有基本的了解，最终的转化目标是 建立强大的基于结构的药物设计（SBDD）计划。 ECS 是一个复杂的脂质网络 配体、受体和代谢酶参与广泛的重要生理过程。 有重要意义的是，靶向 CB2 可能有助于治疗 炎症、疼痛、神经系统疾病和成瘾。与其他 G 蛋白偶联受体一样 (GPCR)，CB2 可以针对不同的配体表现出优先的信号事件。这个功能性的 选择性提供了改进治疗方法、改善有益特性的机会，以及 减少副作用的责任。该研究将为设计和开发提供结构基础 药理学上不同的 CB2 选择性化合物作为有用的生物探针和/或先导物 治疗学的未来发展。为了加强我们获得高质量晶体结构的努力，我们应 使用精心设计的配体，对 CB2 具有高亲和力和选择性，并且还能够 受体结合结构域处或附近的紧密附着及其形成可结晶的能力 配体-受体复合物。该研究有三个具体目标：（1）设计和合成新颖的不可逆 配体代表具有不同功能特征的 CB2 选择性化合物的关键类别。 (2) 广泛 对新合成的配体进行表征，以鉴定具有药理学作用的化合物 不同的特征，包括部分激动剂、反向激动剂、中性拮抗剂和变构剂 调制器。候选结晶及其化学衍生物也将被表征为 使用功能测定的可逆结合性质。 (3) 对CB2配体结合有清晰的认识 通过确定几种受体-配体复合物的 3-D 结构来确定位点。为了实现这些目标， 将解决一些晶体结构，以更好地理解分子识别、信号传导，并协助 设计新颖的化合物，然后可以作为下一代先导化合物和药物的原型 候选人。