Cannabinergic Ligands and Drugs

大麻能配体和药物

基本信息

批准号：
8053849
负责人：
Alexandros Makriyannis
金额：
$ 35.17万
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/8053849
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）：这是一个项目（DA007215-14）的竞争性更新，其目标是通过合成旨在调节关键大麻能蛋白功能的新型配体来确定大麻能活性的结构要求。其中包括两种大麻素受体（CB1、CB2）、内源性大麻素失活酶（FAAH、MGL）和转运系统（AT）。该项目导致了目前研究界广泛使用的关键大麻能配体以及新药物先导物的开发。该领域的最新发展促使我们扩大了该项目的范围，将单酰基甘油脂肪酶（MGL）作为一种新型大麻能靶点，以及氮杂环丁烷类似物（一种有前途的新型 CB1 拮抗剂），从而可以开发具有改进药理学作用的新型配体和药物概况和更广泛的治疗用途。我们还在加紧努力开发改进的 2AG 类似物和探针，这一目标尚未在该领域得到应有的重视。我们的药物设计和合成工作包括三种方法：1）具有改善的水溶性和外周作用的新型大麻素类似物。这将通过在大麻素侧链和三环结构中引入杂原子来实现。 2）新型2-花生四烯酰甘油（2AG）和花生四烯酰乙醇胺（AEA）类似物，具有明确的构象。 3) 氮杂环丁烷类似物代表一类新型 CB1 拮抗剂，具有改善的药理学特性。我们将从理论上并通过溶液和膜中的高分辨率核磁共振研究最成功的新型化合物的立体电子和物理化学性质。此外，配体-受体相互作用的性质将通过 CB1 和 CB2 受体模型进行探索。所有新化合物都将测试其对 CB1 和 CB2 的亲和力和功能特性（作为激动剂、拮抗剂或反向激动剂），同时内源性大麻素类似物也将作为 FAAH、MGL 和 AT 的底物或抑制剂进行评估。最成功的化合物穿过血脑屏障的能力将在体内测定。关键化合物的体内评估将免费合作进行。公共卫生相关性开发抗击药物滥用及其各种附带不良影响的药物对于 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剂会带来严重的滥用可能性，并导致开发出低滥用可能性或无滥用可能性的镇痛药物。该申请的长期目标是开发：（a）用于治疗大麻、尼古丁和兴奋剂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。