| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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Purity: ≥98%
JZL195 is a potent, selective and efficacious dual FAAH/MAGL (fatty acid amide hydrolase/monoacylglycerol lipase) inhibitor with IC50 of 13 nM and 19 nM for mouse brain FAAH and MAGL respectively. JZL195 exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. In addition, JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.
| Targets |
Fatty Acid Amide Hydrolase (FAAH) (IC50 = 8 nM, purified enzyme assay; IC50 = 14 nM, mouse brain membrane assay) [1]
Monoacylglycerol Lipase (MAGL) (IC50 = 4 nM, purified enzyme assay; IC50 = 6 nM, mouse brain membrane assay) [1] Fatty Acid Amide Hydrolase (FAAH) [2] Monoacylglycerol Lipase (MAGL) [2] |
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| ln Vitro |
FP-Rh labeling of mouse brain FAAH and MAGL is nearly completely blocked by JZL195 at concentrations as low as 100 nM (IC50 values of 13 and 19 nM, respectively)[1]. According to competitive ABPP assays, JZL195 inhibits the rat and human FAAH and MAGL enzymes with IC50 values in the range of ≈10-100 nM[1].
1. Purified FAAH and MAGL enzymes were used for activity assays. JZL195 inhibited FAAH with an IC50 of 8 nM and MAGL with an IC50 of 4 nM. In mouse brain membrane homogenates, the IC50 values for FAAH and MAGL were 14 nM and 6 nM, respectively. The drug showed no significant inhibition of other related enzymes (e.g., acetylcholinesterase, cyclooxygenase-1/2) at concentrations up to 10 μM, indicating high selectivity [1] 2. Mouse peritoneal macrophages were treated with JZL195 (1 μM) for 1 hour, followed by stimulation with lipopolysaccharide (LPS). The drug significantly reduced LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6) by approximately 40-50% compared to the control group, without affecting cell viability [2] 3. In mouse brain tissue homogenates, incubation with JZL195 (1 μM) for 30 minutes significantly increased the levels of endocannabinoids anandamide (AEA) by 2.3-fold and 2-arachidonoylglycerol (2-AG) by 3.1-fold, consistent with its dual inhibitory effect on FAAH and MAGL [1] |
| ln Vivo |
In the tail immersion assay, JZL195 (20 mg/kg; ip) elicits an antinociceptive response[1].
1. C57BL/6 mice were administered JZL195 via intraperitoneal injection (1-10 mg/kg). At 1 hour post-administration, brain levels of AEA and 2-AG were dose-dependently increased, with maximum increases of 3.5-fold (AEA) and 4.2-fold (2-AG) at 10 mg/kg. The drug significantly reduced acetic acid-induced writhing responses (ED50 = 3.2 mg/kg) and formalin-induced paw licking (inhibition of 65% at 10 mg/kg), indicating analgesic activity [1] 2. In the hot plate test, intraperitoneal injection of JZL195 (5 mg/kg) significantly prolonged thermal pain latency in mice by 45% at 1 hour post-administration, with the effect lasting for up to 4 hours [1] 3. A murine inflammatory pain model was established by intraplantar injection of complete Freund's adjuvant (CFA). Intraperitoneal administration of JZL195 (3 mg/kg) daily for 7 days significantly reduced CFA-induced mechanical allodynia (paw withdrawal threshold increased by 60%) and thermal hyperalgesia (pain latency prolonged by 55%) compared to the vehicle group. The drug also reduced inflammatory cell infiltration and TNF-α/IL-6 levels in paw tissue [2] 4. JZL195 (5 mg/kg, i.p.) did not induce significant sedation or motor coordination impairment in mice, as evaluated by the open field test and rotarod test, indicating a favorable safety profile at therapeutic doses [1] |
| Enzyme Assay |
1. FAAH activity assay: Purified recombinant FAAH was incubated with different concentrations of JZL195 and the fluorescent substrate arachidonoyl-7-amino-4-methylcoumarin (AAMC) in reaction buffer. After incubation at 37℃ for 30 minutes, the fluorescence intensity of the released 7-amino-4-methylcoumarin was measured to calculate enzyme activity inhibition and IC50 value [1]
2. MAGL activity assay: Purified MAGL was mixed with JZL195 of various concentrations and the substrate 4-nitrophenyl myristate in assay buffer. The reaction was conducted at 37℃ for 60 minutes, and the absorbance at 405 nm was detected to quantify the release of 4-nitrophenol, thereby determining the inhibitory effect and IC50 of JZL195 on MAGL [1] 3. Brain membrane enzyme assay: Mouse brain membranes were prepared and homogenized in ice-cold buffer. The homogenate was incubated with JZL195 and specific substrates for FAAH or MAGL. After incubation at 30℃ for 45 minutes, the reaction was terminated, and the products were extracted and analyzed by liquid chromatography-mass spectrometry (LC-MS) to measure enzyme activity and calculate IC50 values [1] |
| Cell Assay |
1. Macrophage culture and cytokine detection: Mouse peritoneal macrophages were isolated and seeded in 24-well plates at a density of 5×10^5 cells/well. After overnight culture, the cells were treated with different concentrations of JZL195 (0.1-10 μM) for 1 hour, then stimulated with 1 μg/mL LPS for 24 hours. The culture supernatant was collected, and the levels of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA) [2]
2. Cell viability assay: Macrophages were treated with JZL195 (0.1-100 μM) for 24 hours. Cell viability was evaluated by the MTT assay, where MTT reagent was added to the wells and incubated for 4 hours, followed by dissolution of formazan crystals and absorbance measurement at 570 nm to confirm non-cytotoxicity of the drug at effective concentrations [2] |
| Animal Protocol |
Animal/Disease Models: Male C57BL/6J mice[1]
Doses: 20 mg/kg Route of Administration: intraperitoneal (ip)injection Experimental Results: Produced a much greater antinociceptive response in the tail immersion assay compared with inhibitors of either FAAH or MAGL alone. 1. Analgesic activity evaluation (acetic acid writhing test): C57BL/6 mice (20-25 g) were randomly divided into groups. JZL195 was dissolved in a mixture of DMSO, Tween 80, and normal saline (1:1:8, v/v/v) and administered intraperitoneally at doses of 1, 3, 5, 10 mg/kg. The vehicle group received the same volume of solvent. Thirty minutes after administration, 0.6% acetic acid was injected intraperitoneally, and the number of writhing responses within 15 minutes was recorded [1] 2. Formalin test: Mice were administered JZL195 (10 mg/kg, i.p.) or vehicle. Thirty minutes later, 20 μL of 5% formalin was injected into the plantar surface of the hind paw, and the paw licking time was recorded in two phases (0-5 minutes and 15-30 minutes) [1] 3. Hot plate test: Mice were placed on a 55℃ hot plate, and the baseline pain latency (time to lick hind paw or jump) was measured. After administration of JZL195 (5 mg/kg, i.p.) or vehicle, pain latency was measured at 15, 30, 60, 120, and 240 minutes post-administration [1] 4. Inflammatory pain model (CFA-induced): Male C57BL/6 mice (22-26 g) were given an intraplantar injection of 20 μL CFA to induce inflammation. JZL195 (3 mg/kg) or vehicle was administered intraperitoneally once daily for 7 days starting from the day of CFA injection. Mechanical allodynia was assessed using von Frey filaments, and thermal hyperalgesia was measured by the Hargreaves test at 1, 3, 5, 7 days post-CFA injection [2] 5. Tissue collection and analysis: After behavioral tests, mice were sacrificed, and brain, paw, and spinal cord tissues were collected. Tissues were homogenized, and endocannabinoid levels (AEA, 2-AG) were measured by LC-MS. Cytokine levels (TNF-α, IL-6) in paw tissue were detected by ELISA [1][2] |
| ADME/Pharmacokinetics |
1. In mice, after intraperitoneal injection of JZL195 (5 mg/kg), the peak plasma concentration (Cmax) was 1.2 μM and the plasma half-life (t1/2) was 2.8 hours. The drug was widely distributed in tissues, with the highest concentration in brain tissue (2.5 μM 1 hour after administration) [1]
2. In mice, after oral administration of JZL195 (10 mg/kg), the bioavailability was 35%, the Cmax was 0.8 μM, and the t1/2 was 3.1 hours [1] |
| Toxicity/Toxicokinetics |
1. At doses up to 30 mg/kg (intraperitoneal injection), JZL195 did not cause significant death or obvious toxic symptoms (e.g., weight loss, behavioral abnormalities) in mice during a 7-day observation period [1]. 2. Mice treated with JZL195 (10 mg/kg, intraperitoneal injection) for 7 consecutive days showed no significant changes in liver and kidney function indicators (ALT, AST, BUN, creatinine) [2]. 3. The plasma protein binding rate of JZL195 in mice was 89% as determined by balanced dialysis [1].
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| References | |
| Additional Infomation |
1. JZL195 is a potent and selective dual inhibitor of FAAH and MAGL, which are two key enzymes responsible for the degradation of endocannabinoids AEA and 2-AG. By simultaneously inhibiting these two enzymes, JZL195 can synergistically increase the level of endocannabinoids in the central nervous system and peripheral tissues, thereby activating cannabinoid receptors (CB1, CB2) and exerting analgesic, anti-inflammatory and anti-anxiety effects [1]. 2. Compared with single FAAH or MAGL inhibitors, JZL195, due to its dual inhibitory mechanism, has shown superior analgesic activity in various pain models, especially in inflammatory pain models. The drug has good tissue penetration, especially in brain tissue, and good safety at therapeutic doses, making it a potential candidate drug for the treatment of chronic pain and inflammatory diseases [1][2]. 3. In inflammatory pain models, JZL195, in addition to its analgesic effect, can also exert anti-inflammatory effects by reducing the production of pro-inflammatory cytokines (TNF-α, IL-6), which may contribute to its therapeutic effect in inflammatory diseases [2].
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| Molecular Formula |
C₂₄H₂₃N₃O₅
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| Molecular Weight |
433.46
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| Exact Mass |
433.163
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| CAS # |
1210004-12-8
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| Related CAS # |
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| PubChem CID |
46232606
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
581.8±50.0 °C at 760 mmHg
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| Flash Point |
305.7±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.632
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| LogP |
5.63
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
605
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QNYRAEKLMNDRFY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H23N3O5/c28-24(32-22-11-9-20(10-12-22)27(29)30)26-15-13-25(14-16-26)18-19-5-4-8-23(17-19)31-21-6-2-1-3-7-21/h1-12,17H,13-16,18H2
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| Chemical Name |
(4-nitrophenyl) 4-[(3-phenoxyphenyl)methyl]piperazine-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 (5.77 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 (5.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3070 mL | 11.5351 mL | 23.0702 mL | |
| 5 mM | 0.4614 mL | 2.3070 mL | 4.6140 mL | |
| 10 mM | 0.2307 mL | 1.1535 mL | 2.3070 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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