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Endocannabinoid Active Sites as Therapeutic Targets

内源性大麻素活性位点作为治疗靶点

基本信息

批准号：
10680368
负责人：
Alexandros Makriyannis
金额：
$ 143.47万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680368
关键词：
Active Sites Affective Affinity Agonist Alcohol dependence Analgesics Arrestins Biological Assay CNR1 gene CNR2 gene Cannabinoids Collaborations Complex Coupled Coupling Cryoelectron Microscopy Dependence Development Diabetic Nephropathy Disease Drug Kinetics Endocannabinoids Funding Future GTP-Binding Proteins Goals Grant In Vitro Inflammatory Laboratories Ligands Liver Fibrosis Mediating Methods Modeling Molecular Molecular Conformation Mus Mutation Nociception Pain Pain management Pathway interactions Periodicity Peripheral Pharmaceutical Preparations Pharmacology Phenotype Property Pulmonary Fibrosis Receptor Signaling Research Residual state Roentgen Rays Signal Transduction Structure Testing Therapeutic Work Yin-Yang addiction analog anandamide antagonist cannabinergic cannabinoid receptor design drug candidate drug development endocannabinoid signaling improved in vitro testing in vivo insight liquid chromatography mass spectrometry mutant novel novel therapeutics open data painful neuropathy pharmacologic positive allosteric modulator preference programs protein structure rational design receptor recruit side effect therapeutic development therapeutic target tool

项目摘要

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT In this Program Project renewal application, we propose to fundamentally expand current understanding of the variable potentially functional modulations of the CB1 and CB2 cannabinoid receptors. During this current period, our work has resulted in the development of a number of key pharmacologically diverse and selective agonists and antagonists for CB1 and CB2 cannabinoid receptors. We also produced detailed information on the structures of these two receptors. Based upon the strengths of this foundational work, we now propose to develop new functionally selective tools for fine tuning CB1 function and for selectively enhancing CB2 actions in vivo. Our work will generate early candidates for the discovery and development of new therapeutic medications. In this renewal, we will elucidate the functional selectivity aspect of CB1 agonists and develop positive allosteric modulators at CB1 that selectively enhance endocannabinoid signaling. We also propose to develop highly selective CB2 agonists to enable studies of CB2 in vivo while limiting the contributions of CB1 that have been associated with undesirable side effects. Additionally, we propose to develop ligands that act as activators of CB2 while also acting as CB1 antagonists. Using such compounds in vivo may lay the groundwork for the development of medications for inflammatory and fibrotic disorders. Our goals will be accomplished through the synthesis of druggable analogs. The design of these ligands will be based on existing structures of the CB1 and CB2 receptors that were developed during the current funding period and by utilizing computational approaches. The work will require detailed molecular pharmacology aimed at studying the signaling of novel compounds accompanied by targeted mutations in CB1 and CB2 to confirm mechanistic underpinnings of pharmacological divergences in signaling. The most efficient novel compounds will be assayed using in vivo approaches aimed at exploring potential therapeutic value. The overall project will provide foundational information on cannabinoid receptor signaling and serve as a basis for the future development of rationally designed, mechanism-based therapeutic medications.

研究及相关-其他项目信息-项目概要/摘要在这个计划项目更新申请中，我们建议从根本上扩展目前对 CB 1和CB 2大麻素受体的可变潜在功能调节。在本报告所述期间，我们的工作导致制定了一些关键的战略， CB 1和CB 2大麻素受体的多种选择性激动剂和拮抗剂。我们还制作了这两种受体结构的详细信息。基于这项基础工作的优势，我们现在建议开发新的功能选择性工具，用于微调CB 1功能并选择性地增强CB 2在体内的作用。我们的工作将产生早期候选人的发现和发展新的治疗药物。在这次更新中，我们将阐明CB 1激动剂的功能选择性方面并在CB 1处开发选择性增强内源性大麻素信号传导的正变构调节剂。我们也我建议开发高选择性的CB 2激动剂，使CB 2的研究在体内，同时限制的贡献与不良副作用相关的CB 1。此外，我们建议开发配体，其作为CB 2的激活剂，同时也作为CB 1的拮抗剂。在体内使用这些化合物可能会导致为炎症和纤维化疾病的药物开发奠定了基础。我们的目标将通过合成药物类似物来实现。这些配体的设计将是基于在当前资助期内开发的CB 1和CB 2受体的现有结构并利用计算方法。这项工作将需要详细的分子药理学，研究伴随CB 1和CB 2靶向突变的新型化合物的信号传导，药理学信号分歧的机制基础。最有效的新化合物将使用旨在探索潜在治疗价值的体内方法进行测定。整个项目将提供大麻素受体信号传导的基础信息，并作为基础为未来开发合理设计的，基于机制的治疗药物。

项目成果

期刊论文数量（222）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Covalent inhibitors of human monoacylglycerol lipase: ligand-assisted characterization of the catalytic site by mass spectrometry and mutational analysis.

DOI：
10.1016/j.chembiol.2008.06.008
发表时间：
2008-08-25
期刊：
Chemistry & biology
影响因子：
0
作者：
Zvonok N;Pandarinathan L;Williams J;Johnston M;Karageorgos I;Janero DR;Krishnan SC;Makriyannis A
通讯作者：
Makriyannis A

Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats.

DOI：
10.3390/ijms24010240
发表时间：
2022-12-23
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner.

DOI：
10.1016/j.neuropharm.2019.107847
发表时间：
2020-03-01
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Henderson-Redmond AN;Nealon CM;Davis BJ;Yuill MB;Sepulveda DE;Blanton HL;Piscura MK;Zee ML;Haskins CP;Marcus DJ;Mackie K;Guindon J;Morgan DJ
通讯作者：
Morgan DJ

Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats.

大麻素CB2受体的选择性激活抑制了用化学治疗剂紫杉醇在大鼠中诱导的神经性伤害受伤。