Cannabimimetic Ligands and Endocannabinoid Active Sites

大麻模拟配体和内源性大麻素活性位点

• 批准号: 8070440
• 负责人: MAKRIYANNIS ALEXANDROS
• 金额: $ 39.83万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8070440
• 关键词: 2-arachidonylglycerol; 3-Dimensional; Active Sites; Address; Affinity; Affinity Chromatography; Agonist; Amides; Amino Acids; Analgesics; Baculoviruses; Benzophenones; Binding; Binding Sites; Biochemical; Brain imaging; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Carbamates; Cell Culture Techniques; Complement; Complex; Development; Dimerization; Docking; Drug Addiction; Endocannabinoids; Enzymes; Epidemic; Epitopes; Fatty Acids; Funding; Glycerol; Goals; Image; Knowledge; Label; Laboratories; Ligand Binding Domain; Ligands; Ligase; Lipase; Medical; Medication Management; Methods; Modeling; Molecular Models; Opioid; Pain; Parents; Peptide Fragments; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Preparation; Principal Investigator; Procedures; Proteins; Pyrazoles; Radiolabeled; Receptor Activation; Resources; Site; Social Values; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; System; Testing; Work; addiction; analog; anandamide; cannabinoid receptor; combat; cost; covalent bond; cyclooxygenase 2; desensitization; design; drug development; drug of abuse; fatty acid amide hydrolase; in vivo; molecular modeling; mutant; novel; programs; radioligand; radiotracer; receptor; receptor expression; research study; single photon emission computed tomography; stem; tool

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.

该项目是全面合作努力的配体/药物开发部分 研究拒绝程序的主持下的内源性大麻素作用部位（PP）。高亲和力 将利用共价和非共价配体来获取活动位点上的详细结构信息 CB1和CB2大麻素受体（CBR）的。为了增强我们开发高CB1配体的能力 或CB2选择性，我们还将测试我们的新颖配体与钥匙互动的能力 内源性大麻素的靶标参与内源性大麻素失活，包括两种水解酶， 脂肪酸酰胺杂化酶（FAAH）和Monacyl甘油甘油连接酶（MGL），氧化酶 环氧合酶-2（COX-2）和Anandamide Transver System（ANT）。配体将用于： （a）探测CB1和CB2结合位点； （b）在体内图像哺乳动物大脑中的CB1受体（成像 法族将是后来的目标）； （c）探索不同类配体类的药物浮雕要求 对于CB1和CB2脱敏以及受体激活，失活和二聚化。新的 化合物代表结构上多样化的大麻能剂，包括经典和非 - 古典大麻素，氨基烷基吲哚，anandamide和2-芳基烯酰胺类似物和吡喃唑类和吡唑 CB1和CB2拮抗剂。配体被设计为可光活化或无电的不可逆探针 或作为高亲和力可逆探针。共价受体标记将在杆状病毒细胞培养中进行 表达表位标记的CB1和CB2的制剂。受体表达，纯化和 表征将利用亲和力色谱和质谱法。有关配体的信息 受体相互作用将用于开发非阿片类药物，非添加性中心和周边 镇痛药以及旨在应对大麻和其他滥用药物的不良影响的药物。 这种药物旨在解决药物成瘾的流行，并具有很高的医学价值，并且 社会利益。