Cannabimimetic Ligands and Endocannabinoid Active Sites

该项目作为全面合作努力的配体/药物开发组成部分， 研究内源性大麻素的作用位点的主持下，一个计划研究（PP）。高亲和力 将利用共价和非共价配体获得活性位点的详细结构信息 CB 1和CB 2大麻素受体（CBRs）。为了提高我们开发高CB1配体的能力， 或CB2选择性，我们还将测试我们的新配体与关键分子相互作用的能力。 参与内源性大麻素失活的内源性大麻素靶标包括两种水解酶， 脂肪酸酰胺水解酶（FAAH）和单酰基甘油连接酶（MGL），氧化酶 环氧合酶-2（考克斯-2）和花生四烯酸转运系统（ANT）。配体将用于： (a)探测CB 1和CB 2结合位点;（B）对哺乳动物脑中的CB 1受体进行体内成像（成像 FAAH将是以后的目标）;（c）探索不同类别配体内的药效学要求 用于CB1和CB2脱敏以及受体活化、失活和二聚化。新 化合物代表结构上不同类别的大麻能药剂，包括经典的和非- 经典的大麻素、氨基烷基吲哚、花生四烯酸和2-花生四烯酸甘油类似物和吡唑 CB1和CB2拮抗剂。配体被设计为可光活化或亲电的不可逆探针 或作为高亲和力可逆探针。将在杆状病毒细胞培养物中进行共价受体标记 表达表位标记的CB 1和CB 2的制剂。受体的表达、纯化和 表征将利用亲和色谱和质谱方法。配体信息- 受体相互作用将用于开发非阿片类药物，非成瘾性中枢和外周 止痛药以及旨在消除大麻和其他滥用药物不良影响的药物。 这些药物旨在解决吸毒成瘾问题，将具有巨大的医疗价值， 社会效益。

This project serves as the ligand/drug development component of a comprehensive collaborative effort to study the endocannabinoid sites of action under the auspices of a Program Reject (PP). High affinity covalent and non-covalent ligands will be utilized to obtain detailed structural information on the active sites of the CB1 and CB2 cannabinoid receptors (CBRs). To enhance our ability to develop ligands with high CB1 or CB2 selectivities, we shall also test our novel ligands for their abilities to interact with key endocannabinoid targets involved in endocannabinoid deactivation including the two hydrolytic enzymes, Fatty Acid Amide Hytlrolase (FAAH) and Monacyl Glycerol Ligase (MGL), the oxidative enzyme Cyclooxygenase-2 (COX-2), and the Anandamide Transport system (ANT). The ligands will be utilized to: (a) probe the CB1 and CB2 binding sites; (b) in vivo image the CB1 receptor in mammalian brains (imaging of FAAH will be a later goal); (c) explore the pharmacophoric requirements within different classes of ligands for CB1 and CB2 desensitization as well as receptor activation, deactivation and dimerization. The new compounds represent structurally diverse classes of cannabinergic agents, including classical and non- classical cannabinoids, aminoalkylindoles, anandamide and 2-arachidonoyl glycerol analogs and pyrazole CB1 and CB2 antagonists. The ligands are designed as photoactivatable or electrophilic, irreversible probes or as high affinity reversible probes. Covalent receptor labeling will be carried out in baculovirus cell culture preparations expressing epitope-tagged CB1 and CB2. Receptor expression, purification and characterization will utilize affinity chromatographic and mass spectroscopic methods. Information on ligand- receptor interactions will be used for the development of non-opioid, non-addictive central and peripheral analgesics, as well as medications designed to combat the ill effects of cannabis and other drugs of abuse. Such medications aim at addressing the drug addiction epidemic and will be of great medical value and social benefit.