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
  • 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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