Global Discovery Chemistry, ‡Neuroscience, and §Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
J Med Chem. 2013 Oct 10;56(19):7590-607. doi: 10.1021/jm4007627. Epub 2013 Sep 18.
Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective antagonists and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.
双重食欲素受体（OXR）拮抗剂（DORAs），如阿莫雷克斯ant（SB-649868）或苏沃雷克斯ant，在几项最近的志愿者和原发性失眠患者临床试验中，显示出对失眠和睡眠障碍的治疗有希望。拮抗 OX1R 和 OX2R 对诱导睡眠的相对贡献仍然存在争议。因此，我们启动了一个药物发现项目，旨在创建 OX2R 选择性拮抗剂和 DORAs。在这里，我们报告说，OX2R 选择性拮抗剂 26 主要通过增加 NREM 睡眠诱导睡眠，而 DORA 苏沃雷克斯ant 主要通过增加 REM 睡眠诱导睡眠。因此，OX2R 选择性拮抗剂也可能对失眠的治疗有益。
