Studies on Cannabinoid Effects and Cannabimimetic Drugs

大麻素效应和大麻模拟药物的研究

基本信息

批准号：
7222010
负责人：
Alexandros Makriyannis
金额：
$ 11.93万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7222010
关键词：
2-arachidonylglycerol AM 1241 AM 251 AM1172 AM356 AM404 AM630 Active Sites Adenylate Cyclase Affinity Affinity Labels Agonist Amino Acids Anabolism Arts Award Binding Binding Sites Biochemical Biochemical Process Biological Biological Assay Biomedical Research Brain CNR1 gene CNR2 gene Cannabinoids Cannabis Abuse Cell Respiration Cell membrane Cells Class Collaborations Communities Complex Computer Simulation Coupled Data Development Disease Drug abuse Endocannabinoids Environment Enzymes Family Family member G-Protein-Coupled Receptors Generations Genomics Goals Image Imaging Device Inflammation Investigation Joints LOX gene Label Laboratories Letters Life Ligands Lipids Lipoxygenase Liquid substance Location Magic Maps Measurement Membrane Mentorship Methods Modeling Molecular Molecular Conformation Mono-S Monoacylglycerol Lipases Multidimensional NMR Techniques Multinuclear NMR Neuromodulator North Carolina Numbers Organ PTGS2 gene Pain Papio Pattern Pharmaceutical Preparations Phosphatidylethanolamine Phospholipase D Physiological Pilot Projects Positron-Emission Tomography Preparation Principal Investigator Process Productivity Property Protein-Lysine 6-Oxidase Proteins Proteomics Public Health Research Research Methodology Resolution Roentgen Rays Sampling Screening procedure Senior Scientist Award Series Signal Transduction Site Solid Solutions Structure System Techniques Technology Testing Therapeutic Transacylase Underrepresented Minority Universities Walkers Water Work affinity labeling analog analytical tool anandamide base biophysical chemistry cannabinoid receptor computational chemistry cyclooxygenase 2 design drug of abuse fatty acid amide hydrolase improved in vivo inhibitor/antagonist interdisciplinary approach liquid chromatography mass spectroscopy metabolomics mutant novel novel strategies pharmacophore phosphatidylethanolamine programs receptor receptor binding receptor structure function research study response reuptake single photon emission computed tomography solid state therapeutic target tool two-dimensional

项目摘要

DESCRIPTION (provided by applicant): This is a request for renewal of my K05 Senior Scientist Award. During the past fifteen years important developments in the field of cannabinoid research have placed it in the center of biomedical research. The K05 Award has allowed me to enhance my scientific activities in this field. It has also facilitated expansion of my mentorship activities, including those directed towards under-represented minorities. Renewal of the Award will make it possible for me to continue this highly productive effort. It will allow me to regularly modernize techniques being used in my laboratory and introduce novel, state of the art technologies, including: a) the use of liquid chromatography/mass spectroscopy (LC/MS) methods for studying the structure of the GPCRs; b) the use of LC/MS methods in projects on targeted proteomics and targeted metabolomics; c) the use of molecular biological and genomics approaches to characterize and modify known endocannabinoid targets, and search for novel ones; d) the continued use of novel multidimensional NMR techniques (liquids and solids) to study key endocannabinoid proteins and their interactions with cannabinergic ligands, and e) the continued development of novel in vivo imaging approaches. The proposed research is directed towards understanding the molecular bases of cannabinoid activity, many of which are elicited through the endogenous cannabinoid biochemical system. This involves two families of endogenous ligands (endocannabinoids) represented by anandamide and 2-arachidonoylglycerol (2-AG), both of which induce their physiological responses by interacting with the two known cannabinoid receptors (CB1 and CB2). Endocannabinoid signaling is also modulated by the biochemical processes involved in the deactivation of endocannabinoid ligands, including the two known hydrolytic enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), the oxidative enzyme cycloxygenase 2 (COX2) and cellular anandamide reuptake processes that remain to be fully characterized. My research program will continue to focus on understanding the structural requirements involved in the interactions of cannabinergic ligands with each of the target proteins. Such information will be utilized in the design of novel first generation ligands and improved later generation analogs. These compounds can serve as medications to treat drug abuse and assist in the resolution of this important public health problem. The work proposed under this Award will involve a multifaceted approach involving ligand design and synthesis, biophysical and computational chemistry, and biochemical experiments. The results should reveal the molecular properties required for cannabinergic activity (the pharmacophore requirements), and assist in the design of more effective ligands which can serve as useful pharmacological tools, imaging agents, or candidate medications to treat addictive disorders and other illnesses.

描述（由申请人提供）：这是续签我的K05高级科学家奖的要求。在过去的十五年中，大麻素研究领域的重要发展将其置于生物医学研究的中心。 K05奖使我能够增强该领域的科学活动。它还促进了我的指导活动的扩展，包括针对代表性不足的少数民族的活动。裁决该奖项将使我有可能继续这项高产的努力。这将使我能够定期将现代化的技术现代化在实验室中使用，并介绍新颖的最先进技术，包括：a）使用液相色谱/质谱法（LC/MS）方法来研究GPCR的结构； b）在靶向蛋白质组学和靶向代谢组学的项目中使用LC/MS方法； c）使用分子生物学和基因组学方法来表征和修饰已知的内源性大麻素靶标，并寻找新颖的靶标； d）继续使用新型多维NMR技术（液体和固体）来研究关键的内源性大麻素蛋白及其与大麻蛋白能配体的相互作用，以及E）持续开发新型体内成像方法。拟议的研究旨在理解大麻素活性的分子碱基，其中许多是通过内源性大麻素生物化学系统引起的。这涉及两个由anandamide和2-芳基二烯丙基甘油（2-AG）代表的内源性配体（内源性大麻素）家族，它们都通过与两个已知的大麻素受体（CB1和CB2）相互作用来诱导其生理反应。 Endocannabinoid signaling is also modulated by the biochemical processes involved in the deactivation of endocannabinoid ligands, including the two known hydrolytic enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), the oxidative enzyme cycloxygenase 2 (COX2) and cellular anandamide reuptake processes that保持充分的特征。我的研究计划将继续专注于理解大麻能配体与每种靶蛋白的相互作用所涉及的结构要求。这些信息将用于新型第一代配体的设计，并改善了后来的类似物。这些化合物可以用作治疗药物滥用并协助解决这一重要公共卫生问题的药物。根据该奖项提出的工作将涉及一种多方面的方法，涉及配体设计和合成，生物物理和计算化学以及生化实验。结果应揭示大麻能活性所需的分子特性（药效团要求），并协助设计更有效的配体，这些配体可以用作有用的药理学工具，成像剂或候选药物来治疗成瘾性疾病和其他疾病。