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化合物38是一种新型的强效且选择性的腺苷A受体拮抗剂,可增强小鼠的觉醒。

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

作者信息

Zhang Hui, Ma Wei-Xiang, Xie Qiong, Bu Li-Fang, Kong Ling-Xi, Yuan Ping-Chuan, Zhou Rong-Hui, Wang Yong-Hui, Wu Lei, Zhu Chen-Yu, Wang Zhi-Lin, Han Jun, Huang Zhi-Li, Wang Yi-Qun

机构信息

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.

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.

出版信息

Acta Pharmacol Sin. 2025 May;46(5):1177-1189. doi: 10.1038/s41401-024-01443-0. Epub 2025 Jan 8.

Abstract

Adenosine A receptor (AR) plays a pivotal role in the regulation of sleep-wake behaviors. We previously reported an AR selective antagonist compound 38 with an IC 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 AR in the wakefulness-promoting effect of compound 38 using AR 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 AR KO mice, suggesting that the arousal-promoting effect of compound 38 was mediated by AR. We conducted immunohistochemistry and selectively ablated AR-positive neurons using cell type-specific caspase-3 expression, which revealed an essential role of AR-positive neurons in the nucleus accumbens shell for the arousal-promoting effect of compound 38. In conclusion, as a novel AR antagonist, compound 38 promotes wakefulness in mice via the AR and exhibits promising applications for further advancements in the field of sleep-wake disorders.

摘要

腺苷 A 受体(AR)在睡眠 - 觉醒行为的调节中起关键作用。我们之前报道了一种 AR 选择性拮抗剂化合物 38,其 IC 值为 29.0 nM。在本研究中,我们研究了其对小鼠睡眠 - 觉醒调节的影响。野生型(WT)小鼠于 9:00 腹腔注射化合物 38(3.3、5.0、7.5、15、30 mg/kg),同时记录脑电图和肌电图。我们发现,给予化合物 38 对促进觉醒具有剂量依赖性作用。为了研究化合物 38 对睡眠反弹的影响,我们进行了 6 小时(13:00 - 19:00)的睡眠剥夺实验。我们发现,给予化合物 38(30 mg/kg)产生了持续 1 小时的促进觉醒作用。随后,我们使用 AR 基因敲除(KO)小鼠及其野生型同窝小鼠探讨了 AR 在化合物 38 促进觉醒作用中的关键作用。我们发现,化合物 38 增强了野生型小鼠的觉醒,但对 AR KO 小鼠没有促觉醒作用,这表明化合物 38 的促觉醒作用是由 AR 介导的。我们进行了免疫组织化学实验,并使用细胞类型特异性的半胱天冬酶 - 3 表达选择性地消融 AR 阳性神经元,结果表明伏隔核壳中的 AR 阳性神经元在化合物 38 的促觉醒作用中起重要作用。总之,作为一种新型的 AR 拮抗剂,化合物 38 通过 AR 促进小鼠觉醒,并在睡眠 - 觉醒障碍领域的进一步发展中展现出有前景的应用。

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