WWL 70
目录号 : GC15074
WWL 70 是一个选择性的 α/β 水解酶结构域 6 (ABHD6) 抑制剂，其 IC50 值为 70nM。
Cas No.:947669-91-2
Sample solution is provided at 25 µL, 10mM.
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WWL 70 is a selective alpha/beta hydrolase domain 6 (ABHD6) inhibitor with an IC50 of 70nM[1]. ABHD6 is a monoacylglycerol hydrolase that regulates lipid metabolism, neural signaling, synaptic plasticity, and immune-inflammatory responses through modulating the endocannabinoid system and AMPA receptor signaling, and its dysfunction is associated with obesity, neurodegenerative diseases, and psychiatric disorders[2][3]. WWL 70 plays an important role in relevant diseases research by inhibiting ABHD6[4][5].
In vitro, WWL 70(10μM, 15min) attenuated the expression of COX-2 and PGES-1/2 leading to the downregulation of the biosynthetic pathways of PGE2 and PGE2-G in LPS-activated mBV2 microglial cells via cannabinoid receptor-independent mechanisms[6].
In vivo,WWL 70 (10mg/kg/day) was intraperitoneally injected into APP/PS1 mice for 30 days, significantly decreasing Aβ levels and neuroinflammation in the hippocampus, enhancing Aβ phagocytosis by microglia, and improving synaptic plasticity and memory function of the mice[4]. Treatment with the selective ABHD6 inhibitor WWL 70(10mg/kg; 3h after surgery and then once daily until day 7; i.p.) significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia, and reduced microglia activation, macrophage infiltration, and the production of nociceptive mediators in the ipsilateral lumbar spinal cord dorsal horn, DRG, and sciatic nerve in CCI-induced Neuropathic pain mice model[7].
References:
[1] Li, W., Blankman, J. L., & Cravatt, B. F. (2007). A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. Journal of the American Chemical Society, 129(31), 9594–9595.
[2] Pusch, L. M., Riegler-Berket, L., Oberer, M., Zimmermann, R., & Taschler, U. (2022). α/β-Hydrolase Domain-Containing 6 (ABHD6)- A Multifunctional Lipid Hydrolase. Metabolites, 12(8), 761.
[3] Lau, D., Tobin, S., Pribiag, H., Nakajima, S., Fisette, A., Matthys, D., Franco Flores, A. K., Peyot, M. L., Murthy Madiraju, S. R., Prentki, M., Stellwagen, D., Alquier, T., & Fulton, S. (2024). ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice. Nature communications, 15(1), 10652.
[4] Xue, Z., Ye, L., Ge, J., Lan, Z., Zou, X., Mao, C., Bao, X., Yu, L., Xu, Y., & Zhu, X. (2023). Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice. Pharmacological research, 194, 106864.
[5] Bottemanne, P., Paquot, A., Ameraoui, H., Alhouayek, M., & Muccioli, G. G. (2019). The α/β-hydrolase domain 6 inhibitor WWL70 decreases endotoxin-induced lung inflammation in mice, potential contribution of 2-arachidonoylglycerol, and lysoglycerophospholipids. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(6), 7635–7646.
[6] Tanaka, M., Moran, S., Wen, J., Affram, K., Chen, T., Symes, A. J., & Zhang, Y. (2017). WWL70 attenuates PGE2 production derived from 2-arachidonoylglycerol in microglia by ABHD6-independent mechanism. Journal of neuroinflammation, 14(1), 7.
[7] Wen, J., Jones, M., Tanaka, M., Selvaraj, P., Symes, A. J., Cox, B., & Zhang, Y. (2018). WWL70 protects against chronic constriction injury-induced neuropathic pain in mice by cannabinoid receptor-independent mechanisms. Journal of neuroinflammation, 15(1), 9.
WWL 70 是一个选择性的 α/β 水解酶结构域 6 (ABHD6) 抑制剂，其 IC50 值为 70nM[1]。ABHD6是一种单酰甘油水解酶，主要通过调节内源性大麻素系统和AMPA受体信号通路，参与脂质代谢、神经信号传导、突触可塑性以及免疫炎症反应，其功能异常与肥胖、神经退行性疾病和精神疾病等多种病理过程相关[2][3]。WWL 70通过抑制ABHD6在相关疾病研究中发挥重要作用[4][5]。
体外实验中，WWL 70（10μM，15分钟）通过大麻素受体非依赖性机制降低了LPS激活的mBV2小胶质细胞中环氧化酶-2（COX-2）和前列腺素E合酶-1/2（PGES-1/2）的表达，进而下调了前列素E₂（PGE₂）及其代谢产物PGE₂-G的生物合成途径[6]。
体内实验中，将WWL 70（10mg/kg/d）腹腔注射APP/PS1小鼠30天，可显著降低海马Aβ水平和神经炎症，增强小胶质细胞对Aβ的吞噬，并改善小鼠突触可塑性和记忆功能[4]。选择性ABHD6抑制剂WWL 70（ 10mg/kg; 术后3h腹腔注射，每日1次，至第7天）显著缓解慢性坐骨神经压迫损伤（CCI）诱导的神经病理性疼痛小鼠模型中的热痛觉过敏和机械性痛觉过敏，并可减少同侧腰段脊髓背角、背根神经节（DRG）和坐骨神经中的小胶质细胞激活、巨噬细胞浸润以及致痛介质的产生[7]。
| Cell experiment [1]: | |
Cell lines | BV2 microglial cells |
Preparation Method | BV2 microglial cells were cultured in complete DMEM containing 5% heat-inactivated fetal bovine serum under humidified 5% CO2 environment. For PGE2 enzyme immunoassay, the cell culture medium was replaced with pre-warmed medium containing the ABHD6 inhibitor WWL 70 (10μM) and incubated for 15min. The cells were treated with 10μM of 2-AG for 15min, followed by addition of 100ng/ml LPS for BV2, or 2ng/ml LPS for primary microglia. After incubation for 18h, the culture medium was collected. Before addition to the enzyme linked immunoassay (EIA), the medium was centrifuged at 5000rpm for 2min with a table top centrifuge to exclude residual cells. |
Reaction Conditions | 10μM; 15min |
Applications | WWL 70 suppressed PGE2 production in LPS-activated microglia. |
| Animal experiment [2]: | |
Animal models | C57BL/6J mice |
Preparation Method | Mice were anesthetized with isoflurane (3.5% for induction and 2.0% for maintenance), and the mid to lower back of the animals along with the dorsal left thigh were shaved and cleaned with iodine and 75% ethanol. Using aseptic procedures, the common sciatic nerve was exposed at the mid-thigh level by blunt dissection. Under a dissection microscope, a nerve segment of 5mm long was separated from the surrounding tissues. Two ligatures of 6–0 sterile silk, spaced 1.0 to 1.5mm apart, were placed around the sciatic nerve. The ligatures were tied until they just constricted the diameter of the nerve, and a brief twitch was observed in the respective hind limb. In sham-operated mice, the sciatic nerve was isolated and exposed without ligation. The muscles and skins were closed with sutures. phor-saline (1:1:18), which was used as a vehicle control. CCI mice were randomly assigned to receive the ABHD6 inhibitor WWL 70 (10mg/kg) or the vehicle control. Drugs were given intraperitoneally (i.p.) 3h after surgery and then once daily until day 7. Animals were sacrificed on day 7, and the sciatic nerve, spinal cord, and DRG were collected for further analysis. |
Dosage form | 10mg/kg/day for 7 days; i.p. |
Applications | WWL 70 significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia, and reduced microglia activation, macrophage infiltration, and the production of nociceptive mediators in the ipsilateral lumbar spinal cord dorsal horn, DRG, and sciatic nerve. |
References: | |
| Cas No. | 947669-91-2 | SDF | |
| 化学名 | 4'-carbamoyl-[1,1'-biphenyl]-4-yl methyl(3-(pyridin-4-yl)benzyl)carbamate | ||
| Canonical SMILES | O=C(N(C)CC1=CC=CC(C2=CC=NC=C2)=C1)OC3=CC=C(C=C3)C4=CC=C(C(N)=O)C=C4 | ||
| 分子式 | C27H23N3O3 | 分子量 | 437.49 |
| 溶解度 | ≥ 14.45mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2858 mL | 11.4288 mL | 22.8577 mL |
| 5 mM | 0.4572 mL | 2.2858 mL | 4.5715 mL |
| 10 mM | 0.2286 mL | 1.1429 mL | 2.2858 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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- Purity: >98.00%
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