2. Academic Validation
  3. Design and Synthesis of Orexin 1 Receptor-Selective Agonists

Design and Synthesis of Orexin 1 Receptor-Selective Agonists

  • J Med Chem. 2023 Apr 27;66(8):5453-5464. doi: 10.1021/acs.jmedchem.2c01773.
Keita Iio 1 2,  Kao Hashimoto 1 3,  Yasuyuki Nagumo 1,  Mao Amezawa 1 2,  Taisei Hasegawa 1 2,  Naoshi Yamamoto 1,  Noriki Kutsumura 1 2 3,  Katsuhiko Takeuchi 4,  Yukiko Ishikawa 1,  Hikari Yamamoto 1 3,  Akihisa Tokuda 1 3,  Tetsu Sato 5,  Yasuo Uchida 5,  Asuka Inoue 5,  Ryuji Tanimura 1 6,  Masashi Yanagisawa 1 7 8,  Hiroshi Nagase 1 2,  Tsuyoshi Saitoh 1 3
Affiliations

Affiliations

  • 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 Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
  • 4 National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.
  • 5 Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
  • 6 Open Innovation Institute, Kyoto University, Yoshida-honmachi, Sakyo-ku, Kyoto 606-8501, Japan.
  • 7 R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
  • 8 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas TX75390, United States.
PMID: 37043436 DOI: 10.1021/acs.jmedchem.2c01773
Abstract

Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OX1R) and orexin 2 receptors (OX2R). Since the discovery that dysfunction of the orexin/OX2R system causes the sleep disorder narcolepsy, several OX2R-selective and OX1/2R dual agonists have been disclosed. However, an OX1R-selective agonist has not yet been reported, despite the importance of the biological function of OX1R. Herein, we report the discovery of a potent OX1R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide [(R)-YNT-3708; EC50 = 7.48 nM for OX1R; OX2R/OX1R EC50 ratio = 22.5]. The OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX1R in mice.

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