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]。