Design and Synthesis of Orexin 1 Receptor-Selective Agonists

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 ore...

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Published in:Journal of medicinal chemistry 2023-04, Vol.66 (8), p.5453-5464
Main Authors: Iio, Keita, Hashimoto, Kao, Nagumo, Yasuyuki, Amezawa, Mao, Hasegawa, Taisei, Yamamoto, Naoshi, Kutsumura, Noriki, Takeuchi, Katsuhiko, Ishikawa, Yukiko, Yamamoto, Hikari, Tokuda, Akihisa, Sato, Tetsu, Uchida, Yasuo, Inoue, Asuka, Tanimura, Ryuji, Yanagisawa, Masashi, Nagase, Hiroshi, Saitoh, Tsuyoshi
Format: Article
Language:English
Subjects:
Animals
Mice
Neuropeptides
Orexin Receptors - agonists
Orexins
Receptors, G-Protein-Coupled
Sleep
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c01773