Modulating Signaling Endocannabinoids and Fatty Acid Amides

抽象的。对这笔赠款支持的工作的补充，这些工作导致了第一个信号的特征 脂肪酸伯胺及其水解酶的水解酶及其信号转导终止 (FAAH)，以及FAAH作为调节内源性大麻素活性的治疗靶点的有效性，我们将 靶向额外的丝氨酸水解酶，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(即花生胺和2-花生四烯基甘油(2-AG))。随着人们对此的担忧 使用COX-2抑制剂治疗慢性疼痛，阿片类药物的易感性(呼吸抑制， 慢性剂量、依赖、便秘的脱敏)，以及促进直接 大麻素类药物的使用(惊厥、运动功能减退、体温过低、依赖)，对治疗靶向的兴趣 内源性大麻素系统现在很强烈。而不是钝化信号受体的靶向(CB1和 Cb2)，对内源性大麻素信号分子的释放或终止的调制已经出现为 一种特别吸引人的治疗方法，它只通过增强活性来避免大麻类副作用 在他们需要的行动地点发出信号。这一发展在很大程度上是我们和我们的研究的结果 我们发现并表征FAAH的合作者，我们为他们提供了第一批抑制剂 这些药物在体内足够有效，足以验证治疗疼痛的靶点，而不具有 大麻或阿片类药物的副作用。我们的持续努力将确定治疗的机会 使用额外的酶抑制剂调节信号转导的疼痛和炎症性疾病 内源性大麻素(ANANDAME和2-AG)，靶向FAAH/MAGL双重抑制剂，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查文库 主要酶类，并使用基于活性的蛋白质图谱(ABPP)来筛选有效的、选择性的抑制剂 未鉴定的丝氨酸水解酶，用于确定其内源作用和作为 治疗靶点。从我们的工作中产生的科学的核心是发现存在，以及 随之而来的作用，是脂肪酸酰胺信号分子。研究继续确定行动地点和 这些脂肪酸酰胺信号分子的内源性作用将被进行，包括那些靶向的 芥酰胺和花生四胺。

Abstract. 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.