食欲素受体拮抗剂治疗失眠症研究进展

Recent advances in orexin receptor antagonists for the treatment of insomnia

发现于1998年的食欲素体系(orexin system),包括两个G-蛋白偶联受体(G-protein coupled receptors,GPCRs):食欲素-1受体(orexin-1 receptor,OX_1R)和食欲素-2受体(orexin-2 receptor,OX_2R),以及两个神经肽激动剂:食欲素-A(orexin A,OX-A)和食欲素-B(orexin B,OX-B)。这一体系与肥胖、焦虑和睡眠紊乱之间的必然联系,使其迅速成为药物研发的热门靶点之一。针对这一体系研发的食欲素受体拮抗剂(orexin receptor antagonists,ORA),在治疗失眠症方面格外引人注目。2014年8月,美国FDA批准了Merck公司研发的苏沃雷生(suvorexant)上市,成为第一个用于治疗失眠症的食欲素受体拮抗剂。本文综述食欲素受体拮抗剂研究的重要进展,主要关注该类药物的化学结构、作用机制以及临床研究现状。

The orexin system was discovered in 1998 with two G-protein coupled receptors（GPCRs）： orexin-1（OX_1R） and orexin-2（OX_2R） receptors that bind the neuropeptides orexin-A（OX-A） and orexin-B（OX-B）. The causal link between the orexin system and obesity, anxiety, and sleep/wake disorders as a potential therapeutic target has drawn much attention in the field of pharmaceuticals. The developments of dual antagonism of the receptors by small molecules are clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has been approved by FDA in August, 2014. The small molecule orexin receptor antagonists（ORA） between January 2010 and August 2017 are summarized in this review and we focus on their chemical structures, mechanism and human clinical trials.