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<p>Adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) plays a pivotal role in the regulation of sleep-wake behaviors. We previously reported an A<sub>2A</sub>R selective antagonist compound <b>38</b> with an IC<sub>50</sub> 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 <b>38</b> (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 <b>38</b> exhibited a dose-dependent effect on wakefulness promotion. To investigate the impact of compound <b>38</b> on sleep&#xa0;rebound, we conducted a 6 h (13:00–19:00) sleep deprivation experiment. We found that administration of compound <b>38</b> (30 mg/kg) produced a wakefulness-promoting effect lasting for 1 h. Subsequently, we explored the critical role of A<sub>2A</sub>R in the wakefulness-promoting effect of compound <b>38</b> using A<sub>2A</sub>R knockout (KO) mice and their WT littermates. We found that compound <b>38</b> enhanced wakefulness in WT mice, but did not have an arousal-promoting effect in A<sub>2A</sub>R KO mice, suggesting that the arousal-promoting effect of compound <b>38</b> was mediated by A<sub>2A</sub>R. We conducted immunohistochemistry and selectively ablated A<sub>2A</sub>R-positive neurons using cell type-specific caspase-3 expression, which revealed an essential role of A<sub>2A</sub>R-positive neurons in the nucleus accumbens shell for the arousal-promoting effect of compound <b>38</b>. In conclusion, as a novel A<sub>2A</sub>R antagonist, compound <b>38</b> promotes wakefulness in mice via the A<sub>2A</sub>R and exhibits promising applications for further advancements in the field of sleep–wake disorders.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月8日

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  • Hui Zhang,
  • Wei-xiang Ma,
  • Qiong Xie,
  • Li-fang Bu,
  • Ling-xi Kong,
  • Ping-chuan Yuan,
  • Rong-hui Zhou,
  • Yong-hui Wang,
  • Lei Wu,
  • Chen-yu Zhu,
  • Zhi-lin Wang,
  • Jun Han,
  • Zhi-li Huang,
  • Yi-qun Wang

摘要

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.