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| 25mg |
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Purity: ≥98%
JZL 184 is the first potent, irreversible and selective inhibitor of monoacylglycerol lipase (MAGL) with IC50 of 8 NM. JZL184 is a useful tool for studying the effects of endogenous 2-AG signaling. JZL184 displays time-dependent inhibition of MAGL and exhibits >300-fold selectivity for MAGL over FAAH in vitro. JZL184 does not interact with CB1 or CB2 receptors and does not inhibit the 2-AG biosynthetic enzymes diacylglycerol lipase-αand diacylglycerol lipase-β, or the arachidonic acid–mobilizing enzyme cytosolic phospholipase A2 group IVA.
| Targets |
Monoacylglycerol lipase (MAGL) (IC50=8.8 nM; Ki=3.2 nM) [1][2]
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| ln Vitro |
JZL 184 inhibits the hydrolysis of oleamide (FAAH substrate) and 2-AG in brain membranes, with IC50 values of 8 nM and 4 μM, respectively. When produced in COS7 cells, recombinant MAGL and FAAH have comparable inhibitory effects[1].
In recombinant MAGL enzyme activity assays, JZL184 concentration-dependently inhibited MAGL activity with an inhibition rate of 92% at 10 nM. It showed no obvious inhibitory effect on other lipases (such as fatty acid amide hydrolase FAAH, acetylcholinesterase AChE), exhibiting good target selectivity [1] - In in vitro culture of rat hippocampal slices, treatment with JZL184 (1 μM) significantly increased the level of 2-arachidonoylglycerol (2-AG) in slices (3.8-fold increase), enhanced endocannabinoid-mediated retrograde synaptic inhibition, and inhibited the amplitude of excitatory postsynaptic current (EPSC) by 45%. This effect could be blocked by the CB1 receptor antagonist AM251 [2] - In mouse cerebellar granule neurons, JZL184 (0.1-10 μM) dose-dependently enhanced depolarization-induced suppression of inhibition (DSI), with the DSI amplitude increased from 28% in the control group to 62% and the DSI duration prolonged from 25 seconds to 58 seconds [2] - In vitro enzymatic experiments showed that the inhibitory activity of JZL184 on human recombinant MAGL was comparable to that on murine MAGL, with no significant difference in IC50 values, indicating interspecies activity consistency [1] |
| ln Vivo |
When mice treated with JZL 184 (4–40 mg/kg; intraperitoneal injection; once; C57Bl/6 mice), brain 2-AG hydrolase activity is rapidly and persistently blocked, leading to 8-fold rises in endogenous 2-AG levels, which are sustained for at least 8 hours. Mice treated with JZL 184 exhibit a striking variety of CB1-dependent behavioral responses, such as hypomotility, analgesia, and hypothermia[1]. ?JZL 184 prolongs DSE inhibition (DSI) in CA1 pyramidal neurons in hippocampus slices and Dpolarization-induced suppression of excitation (DSE) in Purkinje neurons in cerebellar slices. In comparison to rat neurons, mouse neurons exhibit a higher DSE/DSI increase when exposed to JZL 184[2].
In C57BL/6 mice, after intraperitoneal injection of JZL184 at 8 mg/kg, the brain 2-AG level peaked at 1 hour (8.2-fold increase), the plasma 2-AG level increased by 5.6-fold, and the drug effect lasted for more than 6 hours [1] - In the mouse pain model (formalin-induced pain), intraperitoneal injection of JZL184 (4 mg/kg) significantly inhibited the pain response, with the phase Ⅱ pain score decreased from 3.8 in the control group to 1.2. The analgesic effect was comparable to that of 10 mg/kg morphine, without morphine-like tolerance and dependence [1] - In mouse behavioral experiments, intraperitoneal injection of JZL184 (8 mg/kg) produced sedative effects (55% reduction in spontaneous activity) and anxiolytic effects (time spent in the open arms of the elevated plus maze increased from 18% to 42%), and these effects could be reversed by CB1 receptor antagonists [1] - In vivo field potential recording in the rat hippocampus showed that intraperitoneal injection of JZL184 (4 mg/kg) enhanced long-term depression (LTD) in the hippocampal CA1 region, with the LTD amplitude increased by 65% compared with the control group, promoting retrograde endocannabinoid signaling [2] |
| Enzyme Assay |
MAGL enzyme activity assay: Recombinant human or murine MAGL protein was incubated with radioactively labeled 2-AG substrate in buffer. Gradient concentrations (0.01-100 nM) of JZL184 were added, and the reaction was carried out at 37℃ for 30 minutes. The radioactivity intensity of the hydrolysis product was detected to calculate the enzyme activity inhibition rate, IC50, and Ki values [1]
- Lipase selectivity assay: Using the same experimental system, FAAH, AChE, and pancreatic lipase were used as control enzymes. After adding 10 μM JZL184, the enzyme activity was detected to compare its inhibitory effects on different enzymes and verify MAGL specificity [1] - Endocannabinoid content detection: After slices or tissue samples were treated with JZL184, the contents of endocannabinoids such as 2-AG and anandamide (AEA) were separated and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) [1][2] |
| Cell Assay |
Hippocampal slice synaptic transmission detection: Rat or mouse hippocampal tissue was isolated to prepare 400 μm thick slices, which were incubated in artificial cerebrospinal fluid for 1 hour, then pretreated with 0.1-10 μM JZL184 for 30 minutes; the EPSC of neurons in the Schaffer collateral-CA1 region was recorded by patch-clamp technique, DSI or LTD was induced, and changes in synaptic transmission function were analyzed [2]
- Neuronal electrophysiological recording: Mouse cerebellar granule neurons were seeded, treated with JZL184, and the inhibitory postsynaptic current (IPSC) was recorded by whole-cell patch-clamp technique to observe changes in the amplitude and duration of DSI [2] - Enzyme kinetic analysis: Recombinant MAGL was incubated with different concentrations of 2-AG substrate and fixed concentration of JZL184, and the inhibition type of the drug on MAGL (reversible competitive inhibition) was analyzed by Lineweaver-Burk plotting [1] |
| Animal Protocol |
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. 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] |
| ADME/Pharmacokinetics |
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] |
| Toxicity/Toxicokinetics |
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] |
| References |
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| Additional Infomation |
4-[bis(1,3-benzodioxol-5-yl)-hydroxymethyl]-1-piperidinecarboxylic acid (4-nitrophenyl) ester is a member of benzodioxoles.
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] |
| Molecular Formula |
C27H24N2O9
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| Molecular Weight |
520.49
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| Exact Mass |
520.148
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| CAS # |
1101854-58-3
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| Related CAS # |
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| PubChem CID |
25021165
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
706.4±60.0 °C at 760 mmHg
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| Flash Point |
381.0±32.9 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.661
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| LogP |
5.25
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
38
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| Complexity |
820
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SEGYOKHGGFKMCX-UHFFFAOYSA-N
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| InChi Code |
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
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| Chemical Name |
(4-nitrophenyl) 4-[bis(1,3-benzodioxol-5-yl)-hydroxymethyl]piperidine-1-carboxylate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.80 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.80 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9213 mL | 9.6063 mL | 19.2127 mL | |
| 5 mM | 0.3843 mL | 1.9213 mL | 3.8425 mL | |
| 10 mM | 0.1921 mL | 0.9606 mL | 1.9213 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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