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Modulating Signaling Endocannabinoids and Fatty Acid Amides

调节信号传导内源性大麻素和脂肪酸酰胺

基本信息

批准号：
10532252
负责人：
DALE L BOGER
金额：
$ 39.94万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10532252
关键词：
2-arachidonylglycerol Address Amides Area Binding Proteins Blood Vessels CNR1 gene CNR2 gene Cannabinoids Catalepsy Characteristics Chronic Constipation Dependence Development Disease Dose Endocannabinoids Enzymes Eye Eye diseases FAAH inhibitor Fatty Acids Funding Opportunities Grant Human Genome Hydrolysis Inflammation Inflammatory Libraries MAGL inhibitor Medical Marijuana Monoacylglycerol Lipases Opioid PTGS2 gene Pain management Pharmaceutical Chemistry Physiological Proteins Proteome Receptor Signaling Role Science Serine Hydrolase Signal Transduction Signaling Molecule Site Therapeutic Validation Vascularization Ventilatory Depression Work Writing activity-based protein profiling anandamide chronic pain management desensitization drug discovery endocannabinoid signaling endogenous cannabinoid system fatty acid amide hydrolase in vivo inhibitor innovation interest lipoprotein lipase marijuana use natural hypothermia neuroprotection new therapeutic target receptor screening side effect therapeutic target tool unpublished works

项目摘要

Complementary to efforts supported by this grant that led to the characterization of the first signaling fatty acid primary amide, its hydrolysis and signaling termination by and discovery of fatty acid amide hydrolase (FAAH), and the validation of FAAH as a therapeutic target modulating the activity of endocannabinoids, we will target additional serine hydrolases that regulate the release or degradation of these key signaling fatty acid- derived endocannabinoids (i.e., anandamide and 2-arachidonylglycerol (2-AG)). With the concerns surrounding the use of COX-2 inhibitors for the treatment of chronic pain, the liabilities of opioids (respiratory depression, desensitization with chronic dosing, dependence, constipation), and the challenges of promoting direct cannabinoid use (catalepsy, hypomotility, hypothermia, dependence), interest in therapeutic targeting of the endocannabinoid system is now intense. Rather than blunt force targeting of the signaling receptors (CB1 and CB2), the modulation of the release or termination of the endocannabinoid signaling molecules has emerged as an especially attractive therapeutic approach that avoids cannabinoid side effects by only potentiating active signaling at their needed sites of action. This development is largely the result of our studies and those of our collaborators with whom we discovered and characterized FAAH, and for which we provided the first inhibitors that were sufficiently efficacious in vivo to validate the target for the treatment of pain without the characteristic cannabinoid or opioid side effects. Our continued efforts will define therapeutic opportunities for the treatment of pain and inflammatory disorders by using inhibitors of additional enzymes regulating the signaling of endocannabinoids (anandamide and 2-AG), targeting dual FAAH/MAGL inhibitors, selective MAGL inhibitors, and selective DAGL-? inhibitors. In these studies we will continue to create targeted screening libraries for this major enzyme class and use activity-based protein profiling (ABPP) to screen for potent, selective inhibitors of uncharacterized serine hydrolases for use in identifying their endogenous roles and potential to serve as therapeutic targets. Central to the science to emerge from our work was the discovery of the presence, and subsequently the role, of fatty acid amide signaling molecules. Studies continuing to define the site of action and endogenous role of such fatty acid amide signaling molecules will be conducted, including those targeting erucamide and arachidonamide.

补充这项赠款支持的努力，导致第一个信号的表征脂肪酸伯酰胺、其水解和信号传导终止以及脂肪酸酰胺水解酶的发现（FAAH），以及FAAH作为调节内源性大麻素活性的治疗靶点的验证，我们将靶向调节这些关键信号脂肪酸- 衍生的内源性大麻素（即，花生四烯酰胺和2-花生四烯甘油（2-AG））。随着人们对考克斯-2抑制剂用于治疗慢性疼痛的用途，阿片类药物（呼吸抑制，脱敏与慢性剂量，依赖性，便秘），以及促进直接的挑战，大麻素使用（僵住症、运动不足、体温过低、依赖），对大麻素治疗靶向的兴趣， endocannabinoid系统is now intense激烈.不是信号传导受体（CB 1和CB 2）的钝力靶向， CB 2），内源性大麻素信号传导分子的释放或终止的调节已经出现，一种特别有吸引力的治疗方法，在它们需要的作用部位发出信号。这一发展主要是我们的研究和我们的研究的结果。与我们合作发现并表征FAAH的合作者，我们为他们提供了第一种抑制剂其在体内足够有效以验证用于治疗疼痛的靶点，而不具有以下特征：大麻素或阿片类副作用。我们的持续努力将确定治疗的机会，疼痛和炎症性疾病通过使用调节以下信号传导的额外酶的抑制剂内源性大麻素（大麻素和2-AG），靶向双重FAAH/MAGL抑制剂，选择性MAGL抑制剂，选择性DAGL-？抑制剂的在这些研究中，我们将继续为此创建靶向筛选文库。主要的酶类，并使用基于活性的蛋白质谱（ABPP）筛选有效的，选择性的抑制剂，未表征的丝氨酸水解酶，用于鉴定它们的内源性作用和作为治疗目标从我们的工作中产生的科学的核心是发现了存在，随后的作用，脂肪酸酰胺信号分子。继续进行确定作用部位的研究，这些脂肪酸酰胺信号分子的内源性作用将被进行，包括那些靶向芥酸酰胺和花生四烯酰胺。