Sci Transl Med：潜在抗失眠新药DORA-22副作用极低

一种新的治疗失眠的药物可促进睡眠而且不会损害认知——损害认知是像唑吡坦(Ambien) 和右佐匹克隆(Lunesta)等标准安眠药物的一种常见的副作用。

10-15%的成年人受到失眠的影响，他们中有三分之一的人因为睡眠障碍而服药。这些药物中的大多数是像唑吡坦（Ambien）和右佐匹克隆（Lunesta）这样的处方药。这些药物可通过作用于GABA受体系统而在大多数的病人中有效地诱导睡眠；GABA是大脑主要的抑制性神经递质。但这些药物也与若干副作用有关，其中包括学习、记忆和注意力持续时间受损。Jason Uslaner与MERCK的一组科学家一起研发了一种叫做DORA-22的新型的促睡眠药物，该药可能会更少地扰乱脑功能。研究成果发表在4月3日的《科学转化医学》（Science Translational Medicine)杂志上。

研究人员在大鼠和恒河猴中用不同剂量的DORA-22与3种其它的抗失眠药物进行了比较，并测试了它们对认知的影响。

该团队发现，这些被测试的动物在服用DORA-22之后不久所完成的学习和注意力任务与它们在服用了某种安慰剂后得到的效果一样好。该药看来能在啮齿类及非人灵长类中促进睡眠而不会引起显著的学习或注意力损害。

DORA-22通过作用于食欲素而起作用；食欲素是由脑中被称作外侧下丘脑部分中的特殊神经细胞所释放的分子。食欲素对帮助人们保持清醒是重要的。以食欲素为标靶可帮助诱导睡眠但却不会抑制大脑中对学习和记忆有重要作用的区域的基因活性。

这些发现表明DORA-22可能是治疗睡眠疾病的一种较好的药物

DOI: 10.1126/scitranslmed.3005213

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Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition

Jason M-Uslaner, Spencer J-Tye, Donnie M-Eddins, Xiaohai Wang, Steven V-Fox, Alan T-Savitz, Jacquelyn Binns, Christopher E-Cannon, Susan L-Garson, Lihang Yao, Robert Hodgson, Joanne Stevens, Mark R. Bowlby, Pamela L-Tannenbaum, Joseph Brunner, Terrence P-Mcdonald, Anthony L-Gotter, Scott D-Kuduk, Paul J-Coleman, Christopher J-Winrow and John J-Renger.

Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)–positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound’s minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity–regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use.

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