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：
7596441
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/7596441
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 Collaborations Communities Complex Computer Simulation Coupled Data Development 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 Organ PTGS2 gene Pain Papio Pattern Pharmaceutical Preparations Phosphatidylethanolamine Phospholipase D Physiological Pilot Projects Positron-Emission Tomography Preparation Principal Investigator Process Productivity Property 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 Transacylase Underrepresented Minority Universities Walkers Water Work addiction affinity labeling analog analytical tool anandamide base biological systems biophysical chemistry cannabinoid receptor computational chemistry cyclooxygenase 2 design drug candidate drug of abuse fatty acid amide hydrolase improved in vivo inhibitor/antagonist interdisciplinary approach liquid chromatography mass spectroscopy meetings 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 solid state nuclear magnetic resonance therapeutic development therapeutic target tool two-dimensional

项目摘要

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.

这是我的 K05 高级科学家奖续展请求。在过去的十五年里，重要的是大麻素研究领域的发展使其成为生物医学研究的中心。这 K05 奖使我能够加强我在这一领域的科学活动。也有利于扩大规模我的指导活动，包括针对代表性不足的少数群体的指导活动。续订奖项将使我能够继续这一卓有成效的努力。它将使我能够定期使我的实验室使用的技术现代化并引入新颖的、最先进的技术，包括： a) 使用液相色谱/质谱 (LC/MS) 方法来研究 GPCR 的结构； b) LC/MS 方法在靶向蛋白质组学和靶向药物项目中的使用代谢组学； c) 使用分子生物学和基因组学方法来表征和修改已知的内源性大麻素目标，并寻找新的目标； d) 继续使用新颖的多维核磁共振技术（液体和固体）研究关键的内源性大麻素蛋白及其与大麻能配体，以及 e) 新型体内成像方法的持续发展。拟议的研究旨在了解大麻素活性的分子基础，其中许多是通过内源性大麻素生化系统引起的。这涉及到两个以 anandamide 和 2-arachidonoylglycerol 为代表的内源性配体（内源性大麻素）家族 (2-AG)，两者都通过与两种已知的大麻素相互作用来诱导其生理反应受体（CB1 和 CB2）。内源性大麻素信号传导也受到生化过程的调节参与内源性大麻素配体的失活，包括两种已知的水解酶：脂肪酶酰胺水解酶 (FAAH) 和单酰甘油脂肪酶 (MGL)、氧化酶环加氧酶 2 (COX2) 和细胞 anandamide 再摄取过程仍有待充分表征。我的研究计划将继续侧重于了解涉及的结构要求大麻能配体与每种靶蛋白的相互作用。此类信息将用于设计新颖的第一代配体和改进的新一代类似物。这些化合物可以起到作为治疗药物滥用并协助解决这一重要公共卫生问题的药物。该奖项提出的工作将涉及多方面的方法，包括配体设计和合成、生物物理和计算化学以及生物化学实验。结果应该揭示大麻能活性所需的分子特性（药效团要求），以及协助设计更有效的配体，这些配体可以作为有用的药理学工具、成像治疗成瘾性疾病和其他疾病的药物或候选药物。