Project 2

项目2

基本信息

批准号：
7612921
负责人：
Anuradha Mahadevan
金额：
$ 24.73万
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：
2009-05-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612921
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 Immune response 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 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.

总体上，滥用药物滥用问题，特别是大麻的广泛使用已集中注意植物大麻的化学和药理学。自从十年以来发现大麻素受体，在大麻素领域取得了很多进展。它有已经确定至少有两种类型的大麻素受体：CB1受体出现中枢神经系统（CMS）和CB2受体的内部和外部。主要在外围。已经发现了两个主要的内源配体，Anandamide（AEA）和 2-芳基酮甘油（2-ARA-GI）。它们也称为内源性大麻素，它们都存在于中央以及外围组织。化合物的几种化学上不同和多样的结构类别没有化学/结构关系的大麻素的配体发现受体。拟议合成研究的目的是生成化学探针，这将有助于了解涉及的机制以及内源性大麻素在CMS和周边。我们的具体目的是（1）开发大麻素的变构调节剂CB1 受体，（2）开发DAGL-A抑制剂，（3）酶选择性抑制剂的发展参与内源性大麻素代谢和（4）供应AEA，2-ara-gi和感兴趣的配体其他项目的研究人员进行进一步的生物测试。模拟的合成将提供内源性大麻素探针用于体外和体内研究，结果可能会指向我们的方向在其他大麻素受体亚型中，揭示了参与脑功能的机制，并导致炎症，疼痛，免疫反应，头部损伤中神经保护区域的治疗药物和其他相关疾病。拟议的研究将有助于我们对药理的理解这种重要的化合物的作用，并在医疗保健领域提供药物。