Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton
Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton
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基于萘骨架的新型食欲素2受体激动剂的设计与合成
DOI：
10.1016/j.bmcl.2022.128530
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Hiroshi Nagase
中科院分区：
文献类型：
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作者：
Tsubasa Hino;Tsuyoshi Saitoh;Yasuyuki Nagumo;Naoshi Yamamoto;Noriki Kutsumura;Yoko Irukayama-Tomobe;Yukiko Ishikawa;Ryuji Tanimura;Masashi Yanagisawa;Hiroshi Nagase
基于该策略，针对OX2R选择性激动剂YNT-185(1)柔性键旋转的限制，设计合成了一系列新型的萘衍生物，并对其对增食欲素受体的激动剂活性进行了评价。1，7-萘衍生物表现出比2，7-萘衍生物更好的激动剂活性，表明1的弯曲形式有利于激动剂的活性。1，7-萘衍生物的构象分析表明，酰胺单元从萘面扭曲出来对活性的提高是重要的。在1，7-萘环的2-位引入甲基有效地提高了活性，从而发现了有效的OX2R激动剂28c(OX2R的EC50=99.21nM，OX1R的EC50=148nM)。通过比较最有效的衍生物28c与激动剂结合的OX2R Cryo-EM SPA结构的活性状态的对接模拟结果，很好地支持了构效关系结果。这些结果为了解增食欲素受体激动剂中药效团的活性构象和定位提供了重要信息，有望成为治疗发作性睡病的化疗药物。
A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of1would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist28c(EC50= 9.21 nM for OX2R, 148 nM for OX1R). The structure–activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative28cwith an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.