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Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice

Acta Pharmacologica Sinica volume 46, pages 1177–1189 (2025)Cite this article

Abstract

Adenosine A2A receptor (A2AR) plays a pivotal role in the regulation of sleep-wake behaviors. We previously reported an A2AR selective antagonist compound 38 with an IC50 value of 29.0 nM. In this study, we investigated its effect on sleep-wake regulation in mice. Wild-type (WT) mice were administered compound 38 (3.3, 5.0, 7.5, 15, 30 mg/kg, i.p.) at 9:00, and electroencephalography and electromyography were simultaneously recorded. We showed that administration of compound 38 exhibited a dose-dependent effect on wakefulness promotion. To investigate the impact of compound 38 on sleep rebound, we conducted a 6 h (13:00–19:00) sleep deprivation experiment. We found that administration of compound 38 (30 mg/kg) produced a wakefulness-promoting effect lasting for 1 h. Subsequently, we explored the critical role of A2AR in the wakefulness-promoting effect of compound 38 using A2AR knockout (KO) mice and their WT littermates. We found that compound 38 enhanced wakefulness in WT mice, but did not have an arousal-promoting effect in A2AR KO mice, suggesting that the arousal-promoting effect of compound 38 was mediated by A2AR. We conducted immunohistochemistry and selectively ablated A2AR-positive neurons using cell type-specific caspase-3 expression, which revealed an essential role of A2AR-positive neurons in the nucleus accumbens shell for the arousal-promoting effect of compound 38. In conclusion, as a novel A2AR antagonist, compound 38 promotes wakefulness in mice via the A2AR and exhibits promising applications for further advancements in the field of sleep–wake disorders.

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Fig. 1
Fig. 2: Compound 38 increases wakefulness and decreases NREM sleep in mice during inactive phase.
Fig. 3: Compound 38 prolongs the mean duration of wakefulness and reduces the transitions of each stage.
Fig. 4: Compound 38 exhibits arousal-promoting effect following SD.
Fig. 5: Compound 38 does not exhibit a wakefulness-promoting effect in A2AR KO mice.
Fig. 6: Effect of compound 38 on c-Fos expression in densely expressed brain regions of A2AR.
Fig. 7: Arousal effect of compound 38 was abolished in A2AR-cre mice with ablated A2AR neurons in the NAc shell.
Fig. 8

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (2022YFA1604504 to YQW), the STI2030-Major Projects (2021ZD0203400 to ZLH), the National Natural Science Foundation of China (82171479 and 81871037 to YQW; 82020108014 and 32070984 to ZLH), the Program for Shanghai Outstanding Academic Leaders (to ZLH), the Shanghai Municipal Science and Technology Major Project, ZJLab (2018SHZDZX01 to ZLH), Lingang Laboratory & National Key Laboratory of Human Factors Engineering Joint Grant (LG-TKN-202203-01 to ZLH), the Research Funds of Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine of IHM (2023CXMMTCM011 to JH), the Major Project of Natural Science Foundation of the Department of Education of Anhui Province (2024AH040169 to JH), the Inheritance and Innovation Research Project of Traditional Chinese Medicine of Anhui Province (2024CCCX016 to JH), the Academic support project for top-notch talents in disciplines of universities in Anhui Province (gxbjZD2022043 to JH) and the Natural Science Foundation of Shanghai (24ZR1414500 to QX).

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  1. These authors contributed equally: Hui Zhang, Wei-xiang Ma, Qiong Xie.

Authors and Affiliations

  1. Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical College, Wuhu, 241002, China

    Hui Zhang, Ping-chuan Yuan & Jun Han

  2. Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Joint International Research Laboratory of Sleep, Fudan University, Shanghai, 200032, China

    Hui Zhang, Wei-xiang Ma, Li-fang Bu, Ling-xi Kong, Ping-chuan Yuan, Zhi-lin Wang, Zhi-li Huang & Yi-qun Wang

  3. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Qiong Xie, Rong-hui Zhou, Yong-hui Wang, Lei Wu & Chen-yu Zhu

  4. Wuhu Modern Technology Research and Development Center of Chinese Herbal Medicine and Functional Food, Anhui College of Traditional Chinese Medicine, Wuhu, 241002, China

    Jun Han

  5. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Zhi-li Huang

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Contributions

HZ and WXM designed the study, conducted the experiments and drafted the manuscript; LFB, LXK and ZLW analysed the data and discussed the experiments; PCY did the animal experiments; QX, RHZ, CYZ, YHW and LW synthesed compound 38; JH and QX discussed the experiments and revised the manuscript; YQW and ZLH designed the study and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jun Han, Zhi-li Huang or Yi-qun Wang.

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Zhang, H., Ma, Wx., Xie, Q. et al. Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice. Acta Pharmacol Sin 46, 1177–1189 (2025). https://doi.org/10.1038/s41401-024-01443-0

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