Structure Function of CB1 Cannabinoid Receptor

 描述(由申请人提供)：内源性大麻素系统的关键蛋白质组分--人大麻素受体1(CB1)的结构-功能表征是本研究提案的中心焦点。它的目的是对CB1功能的结构基础有一个基本的理解，最终的翻译目标是建立一个基于实验确定的三维结构的健壮的基于结构的药物设计(SBDD)程序。内源性大麻素系统是一个由脂质配体、受体和代谢酶组成的复杂网络，参与广泛的重要生理过程，包括伤害性感受、炎症、睡眠和药物成瘾。与其他G蛋白偶联受体一样，CB1可以在不同的配体上表现出优先的信号事件。这种功能选择性提供了发现新药物的机会，这些药物具有更好的药理特性、更好的治疗特性和更少的副作用。该研究将为功能分明系统的设计和开发提供结构基础 CB1选择性化合物作为有用的药理工具和/或未来治疗学发展的先导。将解决几个晶体结构，以更好地了解分子识别、信号传递，并帮助设计新的化合物，这些化合物可以作为下一代线索和候选药物的原型。这项研究有三个具体的目标：(1)设计和合成代表关键类别的大麻能配体的共价配体，这些配体已被证明具有不同的功能谱；(2)通过求解几个受体-配体复合体的三维结构来更好地了解CB1的邻位结合位点；(3)通过求解CB1信号复合体的结构来更好地了解CB1的活性状态。

 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.