Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring
Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring
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基于四氢化萘结构的食欲素 2 受体选择性和双重食欲素受体激动剂的发现：通过四氢化萘环上的手性切换受体选择性
DOI：
10.1016/j.bmcl.2022.128555
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hiroshi Nagase
中科院分区：
文献类型：
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作者：
Keita Iio;Tsuyoshi Saitoh;Ryuichiro Ohshita;Tsubasa Hino;Mao Amezawa;Yoshiaki Takayama;Yasuyuki Nagumo;Naoshi Yamamoto;Noriki Kustumura;Yoko Irukayama-Tomobe;Yukiko Ishikawa;Ryuji Tanimura;Masashi Yanagisawa;Hiroshi Nagase
基于萘型食欲素受体激动剂5的结合模式，设计并合成了一系列1-氨基四氢萘衍生物，并评价了它们对食欲素受体的激动活性。在1-氨基四氢萘骨架上引入N-甲基-（3-甲氧基苯基）乙酰胺单元，可显著增强激动剂的效力。6的不对称合成表明，具有（S）-1-氨基四氢萘骨架的（-）-6显示出OX 2 R选择性激动剂活性（对OX 2 R的EC 50 = 2.69 nM，OX 1 R/OX 2 R = 461），而其对映体（R）-（+）-6显示出有效的OX 1/2 R双重激动剂活性（对OX 1 R的EC 50 = 13.5 nM，对OX 2 R的EC 50 = 0.579 nM，OX 1 R/OX 2 R = 23.3）。这些结果表明，酰胺侧链相对于四氢化萘支架的向上取向（S-构型）对于OX 2 R活化将是选择性的，并且向下取向（R-构型）对于双重激动剂活性将是显著的。据我们所知，迄今为止还没有关于激动剂结构上的一个碳中心的立体化学调节食欲素受体选择性的报道。我们的研究结果将为OX 1 R选择性激动剂的开发提供重要信息。
A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist5and their agonist activities against orexin receptors were evaluated. The introduction ofN-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of6revealed that (–)-6having a (S)-1-amino-tetralin skeleton showed a OX2R selective agonist activity (EC50= 2.69 nM for OX2R, OX1R/OX2R = 461) yet its enantiomer (R)-(+)-6showed a potent OX1/2R dual agonist activity (EC50= 13.5 nM for OX1R, 0.579 nM for OX2R, OX1R/OX2R = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OX2R activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OX1R selective agonists.