JZL184

Monoacylglycerol lipase (MAGL) (IC50=8.8 nM; Ki=3.2 nM) [1][2]

JZL 184 抑制脑膜中油酰胺（FAAH 底物）和 2-AG 的水解，IC50 值分别为 8 nM 和 4 μM。当在 COS7 细胞中产生时，重组 MAGL 和 FAAH 具有相当的抑制效果[1]。

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重组MAGL酶活性实验中，JZL184 浓度依赖性抑制MAGL活性，10 nM浓度时抑制率达92%，且对其他脂肪酶（如脂肪酸酰胺水解酶FAAH、乙酰胆碱酯酶AChE）无明显抑制作用，靶点选择性良好[1]
- 大鼠海马脑片体外培养中，JZL184（1 μM）处理可显著升高脑片内2-花生四烯酰甘油（2-AG）水平（升高3.8倍），增强内源性大麻素介导的逆行突触抑制，抑制兴奋性突触后电流（EPSC）幅度达45%，该效应可被CB1受体拮抗剂AM251阻断[2]
- 小鼠小脑颗粒神经元中，JZL184（0.1-10 μM）可剂量依赖性增强 depolarization-induced suppression of inhibition（DSI），DSI幅度从对照组的28%升至62%，延长DSI持续时间（从25秒延长至58秒）[2]
- 体外酶学实验显示，JZL184 对人重组MAGL的抑制活性与鼠源MAGL相当，IC50值无显著差异，提示物种间活性一致性[1]

当小鼠接受 JZL 184（4-40 mg/kg；腹腔注射；一次；C57Bl/6 小鼠）治疗时，大脑 2-AG 水解酶活性被快速且持续地阻断，导致内源性 2-AG 水平上升 8 倍，持续至少8小时。使用 JZL 184 治疗的小鼠表现出多种惊人的 CB1 依赖性行为反应，例如运动不足、镇痛和体温过低[1]。 JZL 184 延长海马切片 CA1 锥体神经元的 DSE 抑制 (DSI) 和小脑切片浦肯野神经元 D 极化诱导的兴奋抑制 (DSE)。与大鼠神经元相比，当暴露于 JZL 184 时，小鼠神经元表现出更高的 DSE/DSI 增加[2]。

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C57BL/6小鼠中，JZL184 以8 mg/kg剂量腹腔注射给药后，脑内2-AG水平在1小时达峰值（升高8.2倍），血浆2-AG水平升高5.6倍，药物作用持续时间超过6小时[1]
- 小鼠疼痛模型（福尔马林致痛）中，JZL184（4 mg/kg，腹腔注射）可显著抑制疼痛反应，Ⅱ相疼痛评分从对照组的3.8降至1.2，镇痛效果与10 mg/kg吗啡相当，且无吗啡样耐受和依赖[1]
- 小鼠行为学实验中，JZL184（8 mg/kg，腹腔注射）可产生镇静效应（自发活动次数减少55%）、抗焦虑作用（高架十字迷宫开放臂停留时间从18%升至42%），且这些效应可被CB1受体拮抗剂逆转[1]
- 大鼠海马体内场电位记录显示，JZL184（4 mg/kg，腹腔注射）可增强海马CA1区长时程抑制（LTD），LTD幅度较对照组升高65%，促进逆行内源性大麻素信号传导[2]

MAGL酶活性测定：重组人或鼠源MAGL蛋白与放射性标记的2-AG底物在缓冲液中孵育，加入梯度浓度（0.01-100 nM）的JZL184，37℃反应30分钟后，检测水解产物的放射性强度，计算酶活性抑制率及IC50、Ki值[1]
- 脂肪酶选择性检测：采用相同实验体系，分别以FAAH、AChE、胰脂肪酶为对照酶，加入10 μM JZL184 后检测酶活性，对比其对不同酶的抑制效果，验证MAGL特异性[1]
- 内源性大麻素含量检测：脑片或组织样本经JZL184 处理后，通过液质联用（LC-MS/MS）技术分离并定量2-AG、花生四烯酸乙醇胺（AEA）等内源性大麻素的含量[1][2]

海马脑片突触传递检测：分离大鼠或小鼠海马组织，制备400 μm厚脑片，在人工脑脊液中孵育1小时后，加入0.1-10 μM JZL184 预处理30分钟；通过膜片钳技术记录Schaffer侧支-CA1区神经元的EPSC，诱导DSI或LTD，分析突触传递功能变化[2]
- 神经元电生理记录：小鼠小脑颗粒神经元接种后，经JZL184 处理，采用全细胞膜片钳技术记录抑制性突触后电流（IPSC），观察DSI的幅度和持续时间变化[2]
- 酶动力学分析：重组MAGL与不同浓度2-AG底物及固定浓度JZL184 孵育，通过Lineweaver-Burk作图法分析药物对MAGL的抑制类型（可逆性竞争抑制）[1]

Animal/Disease Models: Male C57Bl/6 mice (6- 8 weeks old, 20-26 g)[1]
Doses: 4 mg/kg, 8 mg/kg, 16 mg/kg, 40 mg/kg
Route of Administration: intraperitoneal (ip)injection; once
Experimental Results: Produced a rapid and sustained blockade of brain 2 -AG hydrolase activity in mice, resulting in 8-fold elevations in endogenous 2-AG levels that were maintained for at least 8 h.

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Pain behavioral experiment: C57BL/6 mice were randomly divided into a control group, a treatment group, and an antagonist group (10 mice per group). The treatment group was given intraperitoneal injection of JZL184 (4 mg/kg, dissolved in 10% DMSO + 90% normal saline), the antagonist group was pre-injected with AM251 (3 mg/kg) followed by JZL184 30 minutes later; the control group was given an equal volume of vehicle. After plantar injection of formalin in mice, the pain response score within 1 hour was recorded [1]
- Sedative and anxiolytic experiments: Mice were randomly grouped and intraperitoneally injected with JZL184 (8 mg/kg). Thirty minutes later, spontaneous activity counting and elevated plus maze test were performed to record relevant behavioral indicators [1]
- In vivo synaptic plasticity experiment: After adaptive feeding, rats were intraperitoneally injected with JZL184 (4 mg/kg). One hour later, craniotomy was performed to record field potentials in the hippocampal CA1 region, and LTD was induced to monitor changes in its amplitude [2]
- Drug metabolism and endocannabinoid detection experiment: Mice were intraperitoneally injected with JZL184 (8 mg/kg) and sacrificed at 0.5, 1, 3, and 6 hours after administration. Brain and plasma samples were collected, and 2-AG content was detected by LC-MS/MS [1]

In vivo pharmacokinetics in mice showed that after intraperitoneal injection of JZL184 (8 mg/kg), the time to peak plasma drug concentration (Tmax) was 30 minutes, the peak concentration (Cmax) was 1.2 μM, and the elimination half-life (t1/2) was 2.4 hours [1]
- The oral bioavailability (16 mg/kg) was 33%, and the brain/plasma drug concentration ratio was 0.8, which could effectively cross the blood-brain barrier [1]
- The drug was mainly metabolized in the liver, and the metabolites had no MAGL inhibitory activity. It was mainly excreted through urine, with an excretion rate of 78% within 24 hours after administration [1]

In acute toxicity experiments, no death was observed in mice after a single intraperitoneal injection of JZL184 at a dose of 100 mg/kg, and the median lethal dose (LD50) was >100 mg/kg [1]
- After long-term administration (8 mg/kg, once daily for 28 days), there were no significant differences in body weight, blood routine, and liver and kidney function indicators (ALT, AST, creatinine, urea nitrogen) between mice and the control group, and no abnormalities were found in pathological sections of major organs [1]
- The plasma protein binding rate was 97%, with no obvious risk of drug-drug interactions (does not inhibit the cytochrome P450 enzyme system) [1]

[1]. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009 Jan;5(1):37-44.

[2]. 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 Pharmacol Exp Ther. 2009 Nov;331(2):591-7.

4-[bis(1,3-benzodioxol-5-yl)-hydroxymethyl]-1-piperidinecarboxylic acid (4-nitrophenyl) ester is a member of benzodioxoles.

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JZL184 is the first highly selective and reversible small-molecule inhibitor of MAGL. It increases endogenous 2-AG levels by inhibiting MAGL-mediated 2-AG hydrolysis, activating CB1/CB2 receptors to exert biological effects [1][2]
- Its analgesic and anxiolytic effects are not accompanied by morphine-like tolerance and dependence, and there are no obvious psychomotor side effects, making it safer than traditional cannabinoid drugs [1]
- In synaptic plasticity regulation, the enhanced retrograde endocannabinoid signaling by JZL184 can regulate the balance of excitatory and inhibitory synaptic transmission, providing a potential target for the treatment of neuropsychiatric diseases (such as anxiety disorders, epilepsy) [2]
- The inhibition of MAGL by JZL184 is consistent among species, and murine, rat, and human MAGL have similar sensitivity to it, which is beneficial for clinical translation research [1]

C27H24N2O9

520.49

520.148

1101854-58-3

25021165

White to off-white solid powder

1.5±0.1 g/cm3

706.4±60.0 °C at 760 mmHg

381.0±32.9 °C

0.0±2.4 mmHg at 25°C

1.661

5.25

132.51

1

9

5

38

820

0

SEGYOKHGGFKMCX-UHFFFAOYSA-N

InChI=1S/C27H24N2O9/c30-26(38-21-5-3-20(4-6-21)29(32)33)28-11-9-17(10-12-28)27(31,18-1-7-22-24(13-18)36-15-34-22)19-2-8-23-25(14-19)37-16-35-23/h1-8,13-14,17,31H,9-12,15-16H2

(4-nitrophenyl) 4-[bis(1,3-benzodioxol-5-yl)-hydroxymethyl]piperidine-1-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.80 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.5 mg/mL (4.80 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.80 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。