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use natural hypothermia neuroprotection new therapeutic target receptor screening side effect therapeutic target tool unpublished works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.

补充所支持的努力的补充，这导致了第一个信号的表征脂肪酸初级酰胺，其水解和脂肪酸酰胺水解酶的水解和信号传导终止（faah），以及FAAH作为一种治疗目标调节内源性大麻素活性的验证，我们将靶向其他丝氨酸水解酶，该水解酶调节这些关键信号脂肪酸的释放或降解 - 衍生的内源性大麻素（即，anandamide和2-芳基甘烯酰甘油（2-AG））。与周围的担忧使用COX-2抑制剂治疗慢性疼痛，阿片类药物的负债（呼吸抑制，通过长期给药，依赖性，便秘脱敏）以及促进直接的挑战大麻素的使用（催眠症，低动力，体温过低，依赖性），对治疗靶向的兴趣内源性大麻素系统现在很强烈。而不是靶向信号受体的钝力（CB1和 CB2），内源性大麻素信号分子的释放或终止的调制已出现为一种特别有吸引力的治疗方法，仅通过增强活性来避免大麻素副作用在其所需的作用部位发出信号。这种发展在很大程度上是我们研究的结果和我们的研究的结果我们发现并描述了FAAH的合作者，并为此提供了第一个抑制剂体内足够有效的，以验证疼痛治疗的靶大麻素或阿片类药物副作用。我们继续努力将定义治疗的治疗机会疼痛和炎症性疾病通过使用调节信号传导的其他酶的抑制剂内源性大麻素（Anandamide和2-AG），靶向双FAAH/MAGL抑制剂，选择性MAGL抑制剂，和选择性dagl-？抑制剂。在这些研究中，我们将继续为此创建有针对性的筛选库主要的酶类别和使用基于活动的蛋白质分析（ABPP）筛选有效的选择性抑制剂未表征的丝氨酸水解酶用于识别其内源性作用和潜力治疗靶标。从我们的工作中脱颖而出的科学的核心是发现存在，并且随后，脂肪酸酰胺信号分子的作用。研究继续定义行动地点和将进行这种脂肪酸酰胺信号分子的内源性作用，包括靶向灰酰胺和蛛网膜胺。