Structure Function of CB1 Cannabinoid Receptor

CB1大麻素受体的结构功能

• 批准号: 10001488
• 负责人: VSEVOLOD KATRITCH
• 金额: $ 71.7万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001488
• 关键词: Address; Affinity; Agonist; Area; Binding Sites; Biological; CNR1 gene; Cannabinoids; Collaborations; Complex; Coupled; Coupling; Crystallization; Development; Drug Addiction; Drug Design; Enzymes; Event; Exhibits; Future; G protein-coupled receptor 50; G-Protein-Coupled Receptors; G-substrate; Generations; Goals; Human; Imidazole; Inflammation; Laboratories; Ligand Binding Domain; Ligands; Lipids; Medical; Metabolic; Molecular; Nociception; Pain management; Pharmaceutical Preparations; Pharmacology; Physiological; Physiological Processes; Play; Positioning Attribute; Preparation; Process; Production; Property; Proteins; Pyrazoles; Research Proposals; Resolution; Role; Signal Transduction; Sleep; Structure; Testing; Therapeutic; Treatment Side Effects; Work; addiction; anandamide; azetidine; base; behavioral study; beta-arrestin; cannabinoid receptor; design; drug candidate; endogenous cannabinoid system; improved; in silico; in vivo; molecular recognition; new technology; novel; novel strategies; programs; prototype; public health relevance; receptor; receptor binding; receptor expression; response; side effect; structural biology; therapeutic development; three dimensional structure; tool

 DESCRIPTION (provided by applicant): Structure-function characterization of a key protein component of the endocannabinoid system, the human cannabinoid receptor 1 (CB1), is the central focus of this research proposal. It aims to develop a fundamental understanding of the structural basis of CB1 function, with the ultimate translational goal of establishing a robust structure-based drug design (SBDD) program based on experimentally determined 3-dimensional structures. The endocannabinoid system is a complex network of lipid ligands, receptors, and metabolic enzymes involved in a wide range of important physiological processes, including nociception, inflammation, sleep, and drug addiction. As with other G protein coupled receptors, CB1 can exhibit preferential signaling events in response to different ligands. This functional selectivity offers the opportunity to discover new medications with improved pharmacological profiles, enhanced therapeutic properties and reduced side effects. The study will provide the structural basis for the design and development of functionally distinct CB1 selective compounds as useful pharmacological tools and/or leads for the future development of therapeutics. 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. The study has three specific aims: (1) Design and synthesize covalent ligands representing key classes of cannabinergic ligands that have been shown to have distinct functional profiles, (2) Develop a better understanding of the CB1 orthosteric binding site by solving the 3D structure of several receptor-ligand complexes, and (3) Develop a better understanding of the CB1 active state by solving the structure of the CB1 signaling complex.

 描述（通过应用提供）：内源性大麻素系统的关键蛋白质成分，即人类大麻素受体1（CB1）的结构功能表征，是该研究建议的中心重点。它旨在建立对CB1函数结构基础的基本理解，其最终转化目标是基于实验确定的3维结构建立可靠的基于结构的药物设计（SBDD）计划。内源性大麻素系统是一个复杂的脂质配体，受体和代谢酶的网络，其中包括各种重要的物理过程，包括伤害感受，注射，睡眠和吸毒。与其他G蛋白偶联受体一样，CB1可以杀死对不同配体的优先信号事件。这种功能选择性为发现具有改进的药物概况，增强的治疗特性和副作用降低的新药物提供了机会。该研究将为设计和开发功能不同的结构基础 CB1选择性化合物是有用的药物工具和/或铅，可用于未来的治疗。将解决几种晶体结构，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，然后可以作为后来一代铅和候选药物的原型。这项研究具有三个具体目的：（1）设计和合成的共价配体，代表大麻素能配体的关键类别，我们被证明具有独特的功能性谱，（2）通过解决CB1正交结合位点更好地理解CB1正常型结合位点，通过求解几个接收器和cb1的cb1 compient cb1 cb cb cb cb cb cb cb c c c comptiction的3D结构进行了更好的了解。