Luo Zhuo-Hui, Guo Jiang-Shan, Pang Shuo, Dong Wei, Ma Jia-Xin, Zhang Li, Qi Xiao-Long, Guan Fei-Fei, Gao Shan, Gao Xiang, Liu Ning, Pan Shuo, Chen Wei, Zhang Xu, Zhang Lian-Feng, Yang Ya-Jun
Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, China.
Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Acta Pharmacol Sin. 2025 Jan;46(1):66-80. doi: 10.1038/s41401-024-01362-0. Epub 2024 Aug 16.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive impairments. Despite the limited efficacy of current treatments for AD, the 1,2,4-oxadiazole structure has garnered significant attention in medicinal chemistry due to its potential impact on mGluR1 and its association with AD therapy. In this study, a series of novel 1,2,4-oxadiazole derivatives were designed, synthesized, and evaluated for the neuroprotective effects in human neuroblastoma (SH-SY5Y) cells. Among all the derivatives tested, FO-4-15 (5f) existed the lowest cytotoxicity and the highest protective effect against HO. Based on these in vitro results, FO-4-15 was administered to 3×Tg mice and significantly improved the cognitive impairments of the AD mice. Pathological analysis showed that FO-4-15 significantly reduced Aβ accumulation, Tau hyper-phosphorylation, and synaptic impairments in the 3×Tg mice. Dysfunction of the CaMKIIα/Fos signaling pathway in 3×Tg mice was found to be restored by FO-4-15 and the necessity of the CaMKIIα/Fos for FO-4-15 was subsequently confirmed by the use of a CaMKIIα inhibitor in vitro. Beyond that, mGluR1 was identified to be a potential target of FO-4-15, and the interaction of FO-4-15 and mGluR1 was displayed by Ca flow increase, molecular docking, and interaction energy analysis. The target of FO-4-15 was further confirmed in vitro by JNJ16259685, a nonselective inhibitor of mGluR1. These findings suggest that FO-4-15 may hold promise as a potential treatment for Alzheimer's disease.
阿尔茨海默病（AD）是最常见的以认知障碍为特征的神经退行性疾病。尽管目前针对AD的治疗效果有限，但1,2,4-恶二唑结构因其对代谢型谷氨酸受体1（mGluR1）的潜在影响以及与AD治疗的关联，在药物化学领域备受关注。在本研究中，设计、合成了一系列新型1,2,4-恶二唑衍生物，并评估了它们在人神经母细胞瘤（SH-SY5Y）细胞中的神经保护作用。在所有测试的衍生物中，FO-4-15（5f）具有最低的细胞毒性和对过氧化氢（HO）的最高保护作用。基于这些体外实验结果，将FO-4-15给予3×Tg小鼠，显著改善了AD小鼠的认知障碍。病理分析表明，FO-4-15显著减少了3×Tg小鼠脑中的β淀粉样蛋白（Aβ）积累、tau蛋白过度磷酸化和突触损伤。发现FO-4-15可恢复3×Tg小鼠中钙/钙调蛋白依赖性蛋白激酶IIα（CaMKIIα）/Fos信号通路的功能障碍，随后通过体外使用CaMKIIα抑制剂证实了CaMKIIα/Fos对FO-4-15作用的必要性。此外，确定mGluR1是FO-4-15的潜在靶点，并通过钙流增加、分子对接和相互作用能分析展示了FO-4-15与mGluR1的相互作用。mGluR1的非选择性抑制剂JNJ16259685在体外进一步证实了FO-4-15的靶点。这些发现表明，FO-4-15有望成为治疗阿尔茨海默病的潜在药物。
