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，人类大麻素受体1（CB 1）的结构-功能表征是本研究提案的中心焦点。它的目的是发展CB 1功能的结构基础的基本理解，与建立一个强大的基于结构的药物设计（SBDD）程序的基础上实验确定的三维结构的最终翻译目标。内源性大麻素系统是脂质配体、受体和代谢酶的复杂网络，参与广泛的重要生理过程，包括伤害感受、炎症、睡眠和药物成瘾。与其他G蛋白偶联受体一样，CB 1可以响应于不同的配体而表现出优先的信号传导事件。这种功能选择性为发现具有改善的药理学特征、增强的治疗特性和减少的副作用的新药提供了机会。该研究将为功能不同的桥梁的设计和开发提供结构依据 CB 1选择性化合物作为有用的药理学工具和/或用于治疗剂的未来发展的线索。几种晶体结构将被解决，以更好地了解分子识别，信号传导，并协助设计新的化合物，然后可以作为原型，为下一代的线索和候选药物。这项研究有三个具体目标：（1）设计和合成代表大麻能配体的关键类别的共价配体，所述大麻能配体已被证明具有不同的功能特征，（2）通过解决几种受体-配体复合物的3D结构来更好地理解CB 1正构结合位点，（3）通过解析CB 1信号复合物的结构，更好地理解CB 1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.