Cannabinergic Ligands and Drugs

大麻能配体和药物

基本信息

批准号：
8263808
负责人：
Alexandros Makriyannis
金额：
$ 7.46万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-03-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8263808
关键词：
2-arachidonylglycerol Active Sites Adverse effects Affinity Agonist Amidohydrolases Analgesics Animals Arachidonic Acids Attention Azetidines Binding Biochemical Biological Assay Blood - brain barrier anatomy Brain CNR1 gene CNR2 gene Cannabinoids Cannabis Abuse Characteristics Cocaine Communities Computer Simulation Computing Methodologies Coupled Cyclic AMP Data Development Drug Design Drug Kinetics Elements Endocannabinoids Environment Enzymes Ethanolamines Evaluation Fatty Acids Generations Glycerol Goals Grant Health Hydrolysis Laboratories Lead Ligands Lipase MAP Kinase Gene Membrane Methods Modeling Modification Molecular Conformation Monoacylglycerol Lipases National Institute of Drug Abuse Nature Opioid Penetration Peripheral Pharmaceutical Preparations Positioning Attribute Preparation Property Proteins Public Health Research Resolution Side Site Solutions Structure Substance abuse problem System Tail Testing Therapeutic Water analog anandamide azetidine base combat cost design drug synthesis enantiomer improved in vivo inhibitor/antagonist mutant nicotine abuse novel novel therapeutics receptor research study reuptake stimulant abuse water solubility

项目摘要

DESCRIPTION (provided by applicant): This is a competing renewal for a project (DA007215-14) whose goal is to identify the structural requirements for cannabinergic activity through the synthesis of novel ligands aimed at modulating the function(s) of key cannabinergic proteins. These include the two cannabinoid receptors (CB1, CB2), the endocannabinoid deactivating enzymes (FAAH, MGL), and the transporter system (AT). This project has led to the development of key cannabinergic ligands currently in wide use by the research community, as well as novel drug leads. Recent developments in the field have motivated us to widen the project's scope to include monoacylglycerol lipase (MGL) as a novel cannabinergic target as well as azetidine analogs a promising new class of CB1 antagonists, allowing for the development of novel ligands and drugs with improved pharmacological profiles and broader therapeutic utility. We are also intensifying our efforts to develop improved 2AG analogs and probes, a goal that has not received due attention in the field. Our drug design and synthesis efforts encompass three approaches: 1) Novel cannabinoid analogs with improved water solubility and peripheral action. This will be accomplished through the introduction of heteroatoms in the cannabinoid side chain and tricyclic ring structures. 2) Novel 2-arachidonoyl glycerol (2AG) and arachidonoylethanolamine (AEA) analogs, with well-defined conformations. 3) Azetidine analogs representing a novel class of CB1 antagonists with improved pharmacological profiles. We shall study the stereoelectronic and physiochemical properties of the most successful novel compounds theoretically and by high-resolution NMR in solution and in membranes. Additionally, the nature of the ligand- receptor interaction will be explored through CB1 and CB2 receptor models. All new compounds will be tested for their affinities and functional properties (as agonists, antagonists or inverse agonists) for CB1 and CB2, while the endocannabinoid analogs will also be evaluated as substrates or inhibitors of FAAH, MGL and AT. The ability of the most successful compounds to cross the blood-brain barrier will be determined in vivo. The in vivo evaluation of key compounds will be carried out collaboratively at no cost to this grant. PUBLIC HEALTH RELEVANCE The development of medications to combat substance abuse and its myriad collateral ill-effects is of primary importance to NIDA and to national public health. Furthermore, the use of opioids as analgesic agents introduces serious abuse potential and invites development of analgesic medications with low or no abuse potential. The long-term goals of this application are to develop: (a) novel therapeutic medications for the treatment of cannabis, nicotine and stimulant abuse and (b) novel non-opioid analgesics devoid of undesirable side effects.

描述（由申请人提供）：这是针对项目（DA007215-14）的竞争更新，其目标是通过合成旨在调节关键大麻蛋白功能功能的新型配体来确定大麻能活性的结构要求。其中包括两个大麻素受体（CB1，CB2），内源性大麻素失活酶（FAAH，MGL）和转运蛋白系统（AT）。该项目导致了研究界广泛使用的主要大麻能配体以及新型药物铅的发展。该领域的最新发展激发了我们扩大该项目的范围，将单酰甘油脂肪酶（MGL）包括在内，作为一种新型的大麻素能靶标，而氮捷径类似物类似物是一种有希望的新型CB1拮抗剂，允许使用新颖的配体和药物开发具有改进的药理学概况和更广泛的较便利性的新颖性。我们还加强了我们开发改进的2AG类似物和探针的努力，这个目标在该领域尚未得到适当关注。我们的药物设计和合成工作涵盖了三种方法：1）新型大麻素类似物，具有改善的水溶性和周围作用。这将通过在大麻素侧链和三环环结构中引入杂原子来实现。 2）新型2-芳基烯酰基甘油（2Ag）和蛛网氨基氨基胺（AEA）类似物，具有明确的构象。 3）代表具有改进药理特征的新型CB1拮抗剂的氮杂类似物。我们将研究最成功的新颖化合物的立体电源和生理化学特性在理论上以及通过溶液和膜中的高分辨率NMR。另外，将通过CB1和CB2受体模型探索配体受体相互作用的性质。所有新化合物的亲和力和功能特性（作为激动剂，拮抗剂或逆激动剂）将用于CB1和CB2，而内源性大麻素类似物也将作为FAAH，MGL和AT的底物或抑制剂评估。最成功的化合物越过血脑屏障的能力将在体内确定。对关键化合物的体内评估将以这笔赠款的价格合作进行。公共卫生相关的药物开发以打击药物滥用及其无数抵押疾病对NIDA和国家公共卫生至关重要。此外，使用阿片类药物作为镇痛药引入了严重的滥用潜力，并邀请开发低或没有滥用潜力的镇痛药。该应用的长期目标是发展：（a）用于治疗大麻，尼古丁和刺激性滥用的新型治疗药物，以及（b）没有不良副作用的新型非阿片类镇痛药。