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

   
@article{APS11247,
	author = {Hui Zhang and Wei-xiang Ma and Qiong Xie and Li-fang Bu and Ling-xi Kong and Ping-chuan Yuan and Rong-hui Zhou and Yong-hui Wang and Lei Wu and Chen-yu Zhu and Zhi-lin Wang and Jun Han and Zhi-li Huang and Yi-qun Wang},
	title = {Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice},
	journal = {Acta Pharmacologica Sinica},
	volume = {46},
	number = {5},
	year = {2025},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11247}
}