Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton

Tsubasa Hino, Tsuyoshi Saitoh, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 of 1 would 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 agonist 28c (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 derivative 28c with 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.

Original languageEnglish (US)
Article number128530
JournalBioorganic and Medicinal Chemistry Letters
StatePublished - Mar 1 2022


  • Agonist
  • Conformational restriction
  • GPCR
  • Naphthalene
  • OX1R
  • OX2R
  • Orexin
  • Orexin receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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