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

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

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8 Scopus citations

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.

Original language	English (US)
Pages (from-to)	5453-5464
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	8
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01773
State	Published - Apr 27 2023

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Iio, K., Hashimoto, K., Nagumo, Y., Amezawa, M., Hasegawa, T., Yamamoto, N., Kutsumura, N., Takeuchi, K., Ishikawa, Y., Yamamoto, H., Tokuda, A., Sato, T., Uchida, Y., Inoue, A., Tanimura, R., Yanagisawa, M., Nagase, H., & Saitoh, T. (2023). Design and Synthesis of Orexin 1 Receptor-Selective Agonists. Journal of Medicinal Chemistry, 66(8), 5453-5464. https://doi.org/10.1021/acs.jmedchem.2c01773

Iio, K, Hashimoto, K, Nagumo, Y, Amezawa, M, Hasegawa, T, Yamamoto, N, Kutsumura, N, Takeuchi, K, Ishikawa, Y, Yamamoto, H, Tokuda, A, Sato, T, Uchida, Y, Inoue, A, Tanimura, R, Yanagisawa, M, Nagase, H & Saitoh, T 2023, 'Design and Synthesis of Orexin 1 Receptor-Selective Agonists', Journal of Medicinal Chemistry, vol. 66, no. 8, pp. 5453-5464. https://doi.org/10.1021/acs.jmedchem.2c01773

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title = "Design and Synthesis of Orexin 1 Receptor-Selective Agonists",

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.",

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

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doi = "10.1021/acs.jmedchem.2c01773",

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T1 - Design and Synthesis of Orexin 1 Receptor-Selective Agonists

AU - Iio, Keita

AU - Hashimoto, Kao

AU - Nagumo, Yasuyuki

AU - Amezawa, Mao

AU - Hasegawa, Taisei

AU - Yamamoto, Naoshi

AU - Kutsumura, Noriki

AU - Takeuchi, Katsuhiko

AU - Ishikawa, Yukiko

AU - Yamamoto, Hikari

AU - Tokuda, Akihisa

AU - Sato, Tetsu

AU - Uchida, Yasuo

AU - Inoue, Asuka

AU - Tanimura, Ryuji

AU - Yanagisawa, Masashi

AU - Nagase, Hiroshi

AU - Saitoh, Tsuyoshi

PY - 2023/4/27

Y1 - 2023/4/27

N2 - 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.

AB - 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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AN - SCOPUS:85152666796

SN - 0022-2623

VL - 66

SP - 5453

EP - 5464

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Design and Synthesis of Orexin 1 Receptor-Selective Agonists

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