Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Nat Chem Biol. 2020 Jun;16(6):667-675. doi: 10.1038/s41589-020-0528-7. Epub 2020 May 11.
N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.
N-酰基乙醇胺（NAEs），包括内源性大麻素大麻酰胺，是大脑中一类重要的信号脂质。缺乏可调节活体内 NAE 生物合成的化学探针，阻碍了对这些脂质生物学作用的理解。本文采用高通量筛选、化学蛋白质组学和靶向脂质组学，报告了 LEI-401 作为一种中枢神经系统活性 N-酰基磷脂酰乙醇胺磷酸二酯酶（NAPE-PLD）抑制剂的发现和特性。LEI-401 降低了神经母细胞瘤细胞和自由活动小鼠大脑中的 NAE 水平，但在 NAPE-PLD KO 细胞和小鼠中则没有。LEI-401 激活了下丘脑-垂体-肾上腺轴并损害了恐惧性消退，从而模拟了大麻素 CB 受体拮抗剂的作用，而该作用可被脂肪酸酰胺水解酶抑制剂逆转。我们的发现突出了 NAPE-PLD 在大脑中 NAE 生物合成中的独特作用，并表明存在一种内源性 NAE 张力来控制情绪行为。
