更新于：2024-11-01

JZL195

更新于：2024-11-01

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名-

靶点

FAAH x MAGL

作用机制

FAAH抑制剂(脂肪酸酰胺水解酶抑制剂)、MAGL抑制剂(单甘油酯脂肪酶抑制剂)

治疗领域-

在研适应症-

非在研适应症-

原研机构

The Scripps Research Institute

在研机构-

非在研机构

The Scripps Research Institute

最高研发阶段无进展临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C24H23N3O5

InChIKeyQNYRAEKLMNDRFY-UHFFFAOYSA-N

CAS号1210004-12-8

关联

100 项与 JZL195 相关的临床结果

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100 项与 JZL195 相关的转化医学

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100 项与 JZL195 相关的专利（医药）

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项与 JZL195 相关的文献（医药）

2024-11-01·Biomedicine & Pharmacotherapy

Modulation of chemotherapy-induced peripheral neuropathy by JZL195 through glia and the endocannabinoid system

Article

作者: Kim, Leejeong ; Nan, Guanghai ; Cha, Myeounghoon ; Lee, Bae Hwan ; Kim, Hee Young

Chemotherapy-induced peripheral neuropathy (CIPN) used to treat cancer, is a significant side effect with a complex pathophysiology, and its mechanisms remain unclear. Recent research highlights neuroinflammation, which is modulated by the endocannabinoid system (ECS) and associated with glial activation, and the role of toll-like receptor 4 (TLR4) in CIPN. This study aimed to investigate the effects of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and explore the connection between cannabinoid receptors and TLR4 in glial cells. A CIPN animal model was developed using cisplatin-injected male C57BL/6 mice. Mechanical and cold allodynia were assessed through von Frey and acetone tests. Western blot analysis was used to examine the expression of catabolic enzymes, cannabinoid receptors, glial cells, and neuroinflammatory factors in the dorsal root ganglia (DRGs) and spinal cord. Immunohistochemistry was used to investigate the colocalization of cannabinoid receptors and TLR4 in glial cells. JZL195 alleviated pain by inhibiting FAAH/MAGL, modulating the ECS and neuroinflammatory factors, and suppressing glial cell activity. Additionally, cannabinoid receptors and TLR4 colocalized with astrocytes and microglia in the spinal cord. This study highlights the therapeutic potential of JZL195 in modulating the ECS and suggests a correlation between cannabinoid receptors and TLR4 in spinal glial cells, providing insight into alleviating pain and neuroinflammation in CIPN.

2024-11-01·Journal of Neurochemistry

Disrupted stress‐induced analgesia in a neuropathic pain state is rescued by the endocannabinoid degradation inhibitor JZL195

Article

作者: Mitchell, Vanessa A ; Atwal, Nicholas ; Vaughan, Christopher W ; Winters, Bryony L ; Sokolaj, Eddy

AbstractAcute stress normally engages descending brain pathways to produce an antinociceptive response, known as stress‐induced analgesia. Paradoxically, these descending pain modulatory pathways are also involved in the maintenance of the abnormal pain associated with chronic neuropathic pain. It remains unclear how stress‐induced analgesia is affected by neuropathic pain states. We therefore examined the impact of a chronic constriction nerve‐injury (CCI) model of neuropathic pain on restraint stress‐induced analgesia in C57BL/6 mice. Thirty minutes of restraint stress produced analgesia in the hotplate thermal nociceptive assay that was less in CCI compared to control mice who underwent a sham‐surgery. In sham but not CCI mice, stress‐induced analgesia was reduced by the opioid receptor antagonist naltrexone. The cannabinoid CB1 receptor antagonist AM281 did not affect stress‐induced analgesia in either sham or CCI mice. Low‐dose pre‐treatment with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195 increased stress‐induced analgesia in CCI but not sham mice. The JZL195 enhancement of stress‐induced analgesia in CCI mice was abolished by AM281 but was unaffected by naltrexone. These findings indicate that the acute opioid‐mediated analgesic response to a psychological stressor is disrupted in a nerve‐injury model of neuropathic pain. Importantly, this impairment of stress‐induced analgesia was rescued by blockade of endocannabinoid breakdown via a cannabinoid CB1 receptor dependent mechanism. These findings suggest that subthreshold treatment with endocannabinoid degradation blockers could be used to alleviate the disruption of endogenous pain control systems in a neuropathic pain state.

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2024-01-01·Journal of experimental pharmacology

Identifying Potential Human Monoacylglycerol Lipase Inhibitors from the Phytoconstituents of Morinda Citrifolia L. Fruits by in silico Pharmacology and in vitro Study.

Article

作者: Fristiohady, Adryan ; Jiranusornkul, Supat ; Ramadhan, Dwi Syah Fitra ; Sadino, Asman ; Saptarini, Nyi Mekar ; Levita, Jutti

BackgroundHuman monoacylglycerol lipase (MGL) is accountable for the hydrolysis of 2-arachidonoylglycerol (2-AG), thus contributing pivotally to neuroprotection because 2-AG is the main source of arachidonic acid, the precursor of prostaglandins production. Inhibiting MGL reduces inflammatory damage in the ischemic brain and enhances cerebral blood flow. Plants have been reported for their neuroprotective effect, such as Morinda citrifolia on pentylenetetrazol (PTZ)-induced kindling seizures in mice, by reducing the seizures and restoring behavioral and biochemical changes, although the mechanism is not described.PurposeTo evaluate the binding affinity and stability of phytoconstituents in M. citrifolia fruits toward human MGL (PDB ID 3PE6), compared to the known MGL inhibitors (JZL195 and ZYH). The in silico pharmacology study was validated by an in vitro study of the phytosterols and the ethanol extract of M. citrifolia fruits (EEMC) towards MGL.MethodsInitially, nine phytoconstituents of M. citrifolia fruits were docked to the catalytic pocket of human MGL (PDB ID: 3PE6), and compounds with the best affinity were subjected to a molecular dynamic (MD) simulation. The in vitro study was performed using the MGL inhibitor screening assay kit.ResultsThe best binding affinity and stability toward human MGL were shown by stigmasterol and beta-sitosterol, and the MM-PBSA total binding energy of stigmasterol and beta-sitosterol to MGL is stronger than that of JZL195 and ZYH. Moreover, beta-sitosterol and EEMC inhibit MGL with an IC₅₀ value of, respectively, 8.10 μg/mL and 196.20 μg/mL, while JZL195 shows an IC₅₀ of 0.028 μg/mL.ConclusionBeta-sitosterol of Morinda citrifolia fruits may have the potential to protect human neurons by occupying the catalytic site of human MGL, thus competitively inhibiting the substrate of the enzyme. However, the inhibitory activity towards human MGL is lower than JZL195.

100 项与 JZL195 相关的药物交易

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