a Drug Discovery and Preclinical Research , Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
Expert Opin Ther Pat. 2017 Oct;27(10):1123-1133. doi: 10.1080/13543776.2017.1344221. Epub 2017 Jun 28.
The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists. A strong rationale exists for orexin agonism in the treatment of narcolepsy with cataplexy. Areas covered: The patent applications from Thomson Reuters Integrity Database added in 2016 are summarized and discussed together with the most important findings published in the scientific literature. Expert opinion: The large number of patents shows the continuing interest in the orexin receptors as targets. The structural scope covered is narrow. Questions about novelty and inventiveness are evident. The additional information published on X-ray structures on both orexin receptors opens new ways of optimizing antagonists. It might also influence the efforts in the identification of orexin receptor agonists. Being potential treatments for narcolepsy with cataplexy.
下丘脑分泌素系统由两种 G 蛋白偶联受体（orexin1 和 orexin2）和两种内源性配体（orexinA 和 orexinB）组成。该系统在进化上高度保守，与觉醒的促进以及焦虑和成瘾障碍有关。此外，其通过 Ox1 受体的激活可引发几种癌细胞系的凋亡。双重下丘脑分泌素受体拮抗剂已成功用于治疗原发性失眠。目前的主要问题是与 Ox1 选择性拮抗剂的临床验证有关。在下 1 型发作性睡病中使用下丘脑分泌素激动剂具有很强的理论基础。
总结了 2016 年从 Thomson Reuters Integrity Database 添加的专利申请，并与科学文献中发表的最重要的发现一起进行了讨论。
大量的专利表明人们对下丘脑分泌素受体作为靶点的持续兴趣。所涵盖的结构范围较窄。新颖性和创造性的问题显而易见。关于两种下丘脑分泌素受体的 X 射线结构的额外信息为优化拮抗剂开辟了新的途径。它也可能影响鉴定下丘脑分泌素受体激动剂的努力，这些激动剂可能成为下 1 型发作性睡病的潜在治疗方法。
