Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) library

Tsuyoshi Saitoh, Mao Amezawa, Jumpei Horiuchi, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Ryuichiro Ohshita, Akihisa Tokuda, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Emi Hasegawa, Takeshi Sakurai, Yasuo Uchida, Tetsu Sato, Hiroaki Gouda, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (−)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.

Original languageEnglish (US)
Article number114505
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Oct 5 2022


  • 1,3,5-Trioxazatriquinane
  • Chemical library
  • GPCR
  • Orexin receptor
  • Sleep
  • Small molecule

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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