Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor |
| |
| Authors: | Naoshi Yamamoto Sayaka Ohrui Takahiro Okada Masahiro Yata Tsuyoshi Saitoh Noriki Kutsumura Yasuyuki Nagumo Yoko Irukayama-Tomobe Yasuhiro Ogawa Yukiko Ishikawa Yurie Watanabe Daichi Hayakawa Hiroaki Gouda Masashi Yanagisawa Hiroshi Nagase |
| |
| Institution: | 1. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan;2. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan;3. School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan |
| |
| Abstract: | 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. |
| |
| Keywords: | Orexin Opioid Nalfurafine YNT-707 4 5-Epoxy ring Morphinan |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
