Design and Synthesis of Orexin 1 Receptor-Selective Agonists

Keita Iio; Kao Hashimoto; Yasuyuki Nagumo; Mao Amezawa; Taisei Hasegawa; Naoshi Yamamoto; Noriki Kutsumura; Katsuhiko Takeuchi; Yukiko Ishikawa; Hikari Yamamoto; Akihisa Tokuda; Tetsu Sato; Yasuo Uchida; Asuka Inoue; Ryuji Tanimura; Masashi Yanagisawa; Hiroshi Nagase; Tsuyoshi Saitoh

doi:10.1021/acs.jmedchem.2c01773

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. Epub 2023 Apr 12.

Authors

Keita Iio^{1

2}, Kao Hashimoto^{1

3}, Yasuyuki Nagumo¹, Mao Amezawa^{1

2}, Taisei Hasegawa^{1

2}, Naoshi Yamamoto¹, Noriki Kutsumura^{1

2

3}, Katsuhiko Takeuchi⁴, Yukiko Ishikawa¹, Hikari Yamamoto^{1

3}, Akihisa Tokuda^{1

3}, Tetsu Sato⁵, Yasuo Uchida⁵, Asuka Inoue⁵, 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 OX_1/2R 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Mice
Neuropeptides*
Orexin Receptors / agonists
Orexins
Receptors, G-Protein-Coupled*
Sleep

Substances

Orexins
Orexin Receptors
Receptors, G-Protein-Coupled
Neuropeptides