Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

• Published in: Bioorganic & medicinal chemistry letters 2017-09, Vol.27 (17), p.4176-4179
• Main Authors: Yamamoto, Naoshi, Ohrui, Sayaka, Okada, Takahiro, Yata, Masahiro, Saitoh, Tsuyoshi, Kutsumura, Noriki, Nagumo, Yasuyuki, Irukayama-Tomobe, Yoko, Ogawa, Yasuhiro, Ishikawa, Yukiko, Watanabe, Yurie, Hayakawa, Daichi, Gouda, Hiroaki, Yanagisawa, Masashi, Nagase, Hiroshi
• Format: Article
• Language: English
• Subjects: 4,5-Epoxy ring; Binding Sites - drug effects; Dose-Response Relationship, Drug; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacology; Humans; Molecular Structure; Morphinan; Morphinans - chemical synthesis; Morphinans - chemistry; Morphinans - pharmacology; Nalfurafine; Opioid; Orexin; Orexin Receptor Antagonists - chemical synthesis; Orexin Receptor Antagonists - chemistry; Orexin Receptor Antagonists - pharmacology; Orexin Receptors - metabolism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; YNT-707
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.07.011

[Display omitted] The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.