Project 2

项目2

基本信息

批准号：
8152626
负责人：
Anuradha Mahadevan
金额：
$ 23.96万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8152626
关键词：
2-arachidonylglycerol Absence of pain sensation Address Affect Allosteric Site Anabolism Area Attention Binding Binding Sites Biochemical Biological Biological Testing Brain CNR1 gene CNR2 gene Cannabinoids Cannabis sativa plant Carbamates Carbon Cardiovascular system Chemicals Chemistry Cognitive Complex Craniocerebral Trauma Development Disease Dissociation Drug abuse Eating Emotional Endocannabinoids Enzyme Inhibitor Drugs Enzyme Inhibitors Equilibrium Experimental Designs Family Fatty Acids Goals Healthcare Hormones Immune response Immunosuppression In Vitro Indoles Inflammation Lead Leptin Libraries Ligands Lipase Literature Lysophospholipids Marijuana Smoking Metabolic Metabolism Methods Neuraxis Pain Participant Peripheral Pharmaceutical Preparations Pharmacology Physiological Play Progress Reports Property Proteomics Research Research Personnel Role Series Serine Hydrolase Signal Transduction System Therapeutic Tissues analog anandamide base cannabinoid receptor complex biological systems design enzyme biosynthesis experience in vivo inhibitor/antagonist insight interest lipoprotein lipase lysophosphatidic acid motor control neuroprotection neurotransmitter release novel phosphonate programs quinoline quinoline analog receptor scaffold tool

项目摘要

The drug abuse problem in general and the widespread use of marijuana in particular have focused attention on the chemistry and pharmacology of the plant Cannabis sativa. In the decade since the discovery of the cannabinoid receptors, much progress has been made in the cannabinoid field. It has been established that there are at least two types of cannabinoid receptors: CB1 receptors which are present both inside and outside the central nervous system (CMS) and CB2 receptors which are found mainly in the periphery. Two main endogenous ligands have been discovered, anandamide (AEA) and 2-arachidonyl-glycerol (2-Ara-GI). Also known as endocannabinoids, they are both present in central as well as peripheral tissues. Several chemically distinct and diverse structural classes of compounds which have no chemical/ structural relationships have been discovered as ligands for the cannabinoid receptors. The goal of the proposed synthetic research is to generate chemical probes which will help in understanding the mechanisms involved and the role of endocannabinoids in the CMS and the periphery. Our Specific Aims are (1) development of allosteric modulators of the cannabinoids CB1 receptors, (2) development of DAGL-a inhibitors, (3) development of selective inhibitors of enzymes involved in endocannabinoid metabolism and (4) supply AEA, 2-Ara-GI and ligands of interest to investigators for the other projects for further biological testing. The synthesis of the analogs will provide endocannabinoid probes for the in vitro and in vivo studies and the results could point us in the direction of other cannabinoid receptor subtypes, reveal mechanisms involved in brain function and lead to therapeutic drugs in the areas of inflammation, pain, immune response, neuroprotection in head injury and other CMS related diseases. The proposed study will help our understanding of the pharmacological action of this important class of compounds and provide drugs in the health care field.

一般的药物滥用问题，特别是大麻的广泛使用，引起了人们对大麻植物化学和药理学的关注。自发现大麻素受体以来的十年间，大麻素领域取得了很大进展。已经确定至少有两种类型的大麻素受体：存在于中枢神经系统（CMS）内部和外部的 CB1 受体和已发现的 CB2 受体主要是在外围。已发现两种主要的内源性配体：花生四烯酸乙醇胺 (AEA) 和 2-花生四烯酰甘油 (2-Ara-GI)。也称为内源性大麻素，它们都存在于中枢和外周组织中。已发现几种化学上不同且结构多样且没有化学/结构关系的化合物可作为大麻素受体的配体。拟议的合成研究的目标是生成化学探针，这将有助于理解所涉及的机制以及内源性大麻素在 CMS 和外周中的作用。我们的具体目标是 (1) 开发大麻素 CB1 受体的变构调节剂，(2) 开发 DAGL-a 抑制剂，(3) 开发参与内源性大麻素代谢的酶的选择性抑制剂，以及 (4) 供应 AEA、2-Ara -研究人员感兴趣的GI和配体用于其他项目以进行进一步的生物测试。类似物的合成将为体外和体内研究提供内源性大麻素探针，其结果可以为我们指明其他大麻素受体亚型的方向，揭示涉及大脑功能的机制，并产生炎症、疼痛领域的治疗药物、免疫反应、头部损伤和其他 CMS 相关疾病中的神经保护。拟议的研究将有助于我们了解这一类重要化合物的药理作用，并为医疗保健领域提供药物。