Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4, 5-epoxy ring for binding with orexin 1 receptor. Issue 17 (1st September 2017)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 17(2017)
• Page Start: 4176
• Page End: 4179
• Publication Date: 2017-09-01
• Subjects: Orexin -- Opioid -- Nalfurafine -- YNT-707 -- 4, 5-Epoxy ring -- Morphinan; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.07.011
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The essential structure of the orexin 1 receptor (OX1 R) antagonist YNT-707 (2 ) was clarified, particularly the roles to OX1 R 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 OX1 R 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 OX1 R 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 OX1 R ligands.