2. Academic Validation
  3. Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice

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

  • Acta Pharmacol Sin. 2025 Jan 8. doi: 10.1038/s41401-024-01443-0.
Hui Zhang # 1 2,  Wei-Xiang Ma # 2,  Qiong Xie # 3,  Li-Fang Bu 2,  Ling-Xi Kong 2,  Ping-Chuan Yuan 1 2,  Rong-Hui Zhou 3,  Yong-Hui Wang 3,  Lei Wu 3,  Chen-Yu Zhu 3,  Zhi-Lin Wang 2,  Jun Han 4 5,  Zhi-Li Huang 6 7,  Yi-Qun Wang 8
Affiliations

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.
  • 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.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 4 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. hanjun@wnmc.edu.cn.
  • 5 Wuhu Modern Technology Research and Development Center of Chinese Herbal Medicine and Functional Food, Anhui College of Traditional Chinese Medicine, Wuhu, 241002, China. hanjun@wnmc.edu.cn.
  • 6 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. huangzl@fudan.edu.cn.
  • 7 Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. huangzl@fudan.edu.cn.
  • 8 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. yiqunwang@fudan.edu.cn.
  • # Contributed equally.
PMID: 39779967 DOI: 10.1038/s41401-024-01443-0
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.

Keywords

A2AR KO mice; A2AR antagonist; Compound 38; arousal-promoting effect; sleep deprivation; sleep–wake states.

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