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Discovery of FO-4-15, a novel 1,2,4-oxadiazole derivative, ameliorates cognitive impairments in 3×Tg mice by activating the mGluR1/CaMKIIα pathway

Acta Pharmacologica Sinica volume 46, pages 66–80 (2025)Cite this article

Abstract

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 H2O2. 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 Ca2+ 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.

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Fig. 1: Screening of the cytotoxicity and anti-H2O2 activity of the 1,2,4-oxadiazole derivatives.
Fig. 2: Determination of the LD50 and anti-H2O2 effects of FO-4-15.
Fig. 3: Behavioral analysis of mice treated with FO-4-15.
Fig. 4: Observation of Aβ pathology in brain tissues of 3×Tg mice.
Fig. 5: Determination of Tau phosphorylation and spines morphology in brain tissues of 3×Tg mice.
Fig. 6: FO-4-15 activates the CaMKIIα signaling pathway in 3×Tg mice.
Fig. 7: Determination of CaMKIIα pathway in vitro.
Fig. 8: Determination of the target of FO-4-15 on 293T cells.
Fig. 9: In vitro target verification of FO-4-15. 10 µM JNJ was applied as the selective inhibitor of mGluR1.

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (2022YFF0710702) and the Beijing Natural Science Foundation (7244343). The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Zhuo-hui Luo, Li Zhang, Xiao-long Qi, Fei-fei Guan & Lian-feng Zhang

  2. 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

    Jiang-shan Guo & Ya-jun Yang

  3. The Laboratory of Neurological Disorders and Brain Cognition, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Shuo Pang

  4. Beijing Engineering Research Center for Experimental Animal Models of Human Diseases, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, China

    Wei Dong, Jia-xin Ma, Shan Gao, Xiang Gao, Ning Liu, Shuo Pan, Wei Chen & Xu Zhang

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  1. Zhuo-hui Luo
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  2. Jiang-shan Guo
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Contributions

LFZ, YJY, and ZHL designed the research plan. YJY and JSG prepared the compounds. ZHL, SPang, WD, FFG, SG, NL, XG, SPan, WC, and XZ prepared the AD mice models. ZHL and SPang performed mice treatment and behavior tests. ZHL, SPang, JXM, XLQ and LZ performed tissue collection, histology analyses, and mechanism exploration. LFZ and YJY audited the experimental procedures. LFZ, YJY, and ZHL analyzed the data, wrote and/or revised the manuscript, and had primary responsibility for the final content. All authors contributed to the article and approved the submitted version.

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Correspondence to Lian-feng Zhang or Ya-jun Yang.

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Luo, Zh., Guo, Js., Pang, S. et al. Discovery of FO-4-15, a novel 1,2,4-oxadiazole derivative, ameliorates cognitive impairments in 3×Tg mice by activating the mGluR1/CaMKIIα pathway. Acta Pharmacol Sin 46, 66–80 (2025). https://doi.org/10.1038/s41401-024-01362-0

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