JZL184 is a potent, selective and irreversible inhibitor of monoacylglycerol lipase (MAGL), which blocks the hydrolysis of 2-arachidonoylglycerol (2-AG) in the brain membrane with an IC50 value of 8nM[1]. JZL184 displays >300-fold selectivity for MAGL than fatty acid amide hydrolase (FAAH)[2]. JZL184 can alleviate neurological impairment after cardiac arrest by regulating mitochondrial transport and lipid droplet accumulation[3].
In vitro, JZL184 (0.01, 0.1, 1μM) treated A549 and H358 cells cultured under hypoxia for 6h inhibited HIF-1α protein expression in hypoxic A549 cells in a dose-dependent manner, but no significant decrease in HIF-1α protein expression was detected in H358 cells[4].
In vivo, JZL184 (16mg/kg) was intraperitoneally injected into mice with cancer-induced bone disease for 35 days, which significantly inhibited cancer-related bone damage, reduced bone tumor growth, reduced the migration and osteolytic characteristics of bone-tropic cancer cells, and prolonged the survival of mice[5]. JZL184 (10mg/kg) was intraperitoneally injected into rats with acute immune stress induced by lipopolysaccharide (LPS) and attenuated the increase of IL-1β, IL-6, TNF-α, and IL-10 in the frontal cortex of rats, but did not attenuate the expression of NFκB inhibitor (IκBa)[6]. JZL184 (40mg/kg) was intraperitoneally injected into transgenic APdE9 mice and significantly reduced the proinflammatory response of microglia in the hippocampus, temporal lobe, and parietal cortex of mice, and reduced the total load of Aβ and its precursors[7].
References:
[1] Long J Z, Li W, Booker L, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects[J]. Nature chemical biology, 2009, 5(1): 37-44.
[2] Pan B, Wang W, Long J Z, et al. Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo [d][1, 3] dioxol-5-yl (hydroxy) methyl) piperidine-1-carboxylate (JZL184) Enhances retrograde endocannabinoid signaling[J]. The Journal of pharmacology and experimental therapeutics, 2009, 331(2): 591-597.
[3] Zhang Q, Zhang C, Lu Y, et al. JZL-184 Alleviate Neurological Impairment through Regulation of Mitochondrial Transfer and Lipid Droplet Accumulation after Cardiac Arrest[J]. Molecular Neurobiology, 2024: 1-17.
[4] Wittig F, Pannenberg L, Schwarz R, et al. Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells[J]. Cells, 2023, 12(19): 2332.
[5] Marino S, de Ridder D, Bishop R T, et al. Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice[J]. EBioMedicine, 2019, 44: 452-466.
[6] Kerr D M, Harhen B, Okine B N, et al. The monoacylglycerol lipase inhibitor JZL 184 attenuates LPS‐induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action[J]. British journal of pharmacology, 2013, 169(4): 808-819.
[7] Pihlaja R, Takkinen J, Eskola O, et al. Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells[J]. Journal of Neuroinflammation, 2015, 12: 1-6.
JZL184是一种有效的，选择性的且不可逆的单酰甘油脂肪酶（MAGL）抑制剂，可阻断脑膜中的2-花生四烯酸甘油酯（2-AG）的水解，IC50值为8nM[1]。JZL184对MAGL的选择性比脂肪酸酰胺水解酶（FAAH）高300倍以上[2]。JZL184能够通过调节线粒体转运和脂滴蓄积减轻心脏骤停后的神经功能损伤[3]。
在体外，JZL184（0.01, 0.1, 1μM）处理缺氧条件下培养的A549、H358细胞6h，以剂量依赖性方式抑制了缺氧A549细胞中HIF-1α蛋白表达，但在H358细胞中未检测到显著的HIF-1α蛋白表达下降[4]。
在体内，JZL184（16mg/kg）通过腹腔注射治疗癌症引起的骨病小鼠35天，显著抑制了癌症相关的骨损伤，减少了骨骼肿瘤生长，降低了骨向性癌细胞的迁移和溶骨特征，延长了小鼠生存期[5]。JZL184（10mg/kg）通过腹腔注射治疗脂多糖（LPS）诱导的急性免疫应激大鼠，减弱了大鼠额叶皮质中IL-1β、IL-6、TNF-α和IL-10的增加，但没有减弱NFκB抑制剂（IκBa）的表达[6]。JZL184（40mg/kg）通过腹腔注射治疗转基因APdE9小鼠，显著降低了小鼠海马、颞叶和顶叶皮质中小胶质细胞的促炎反应，并减少了Aβ的总负荷及其前体[7]。