@article{c1bc90eb5e254180bb8f80c3c56b019a,
title = "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",
abstract = "A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (–)-6 having 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)-(+)-6 showed 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.",
keywords = "Agonist, Diarylsulfonamide, OX1R, OX2R, Orexin, Orexin receptor, Tetraline",
author = "Keita Iio and Tsuyoshi Saitoh and Ryuichiro Ohshita and Tsubasa Hino and Mao Amezawa and Yoshiaki Takayama and Yasuyuki Nagumo and Naoshi Yamamoto and Noriki Kutsumura and Yoko Irukayama-Tomobe and Yukiko Ishikawa and Ryuji Tanimura and Masashi Yanagisawa and Hiroshi Nagase",
note = "Funding Information: This work was supported by JSPS KAKENHI (18K14352, 19H03428, 20K05743, 21B209 to T.S.; 16H05098, 20H03361 to H.N. Y.N. T.S.; 19K07314 to Y.I-T.), Japan Foundation for Applied Enzymology (16H007 to T.S.), AMED under Grant Number JP21zf0127005, Toray Industries, Inc, and the grant of collaborative research between University of Tsukuba and Toyota Motor Corporation. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan. Finally, the authors would like to thank K. Takeuchi (National Institute of Advanced Industrial Science and Technology (AIST)) for the technical assistance of X-ray data analysis of compound (?)-13. Funding Information: This work was supported by JSPS KAKENHI ( 18K14352 , 19H03428 , 20K05743 , 21B209 to T.S.; 16H05098 , 20H03361 to H.N., Y.N., T.S.; 19K07314 to Y.I-T.), Japan Foundation for Applied Enzymology ( 16H007 to T.S.), AMED under Grant Number JP21zf0127005 , Toray Industries, Inc, and the grant of collaborative research between University of Tsukuba and Toyota Motor Corporation. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan. Finally, the authors would like to thank K. Takeuchi (National Institute of Advanced Industrial Science and Technology (AIST)) for the technical assistance of X-ray data analysis of compound (–)- 13 . Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = mar,
day = "15",
doi = "10.1016/j.bmcl.2022.128555",
language = "English (US)",
volume = "60",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
}