Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

Naoshi Yamamoto; Sayaka Ohrui; Takahiro Okada; Masahiro Yata; Tsuyoshi Saitoh; Noriki Kutsumura; Yasuyuki Nagumo; Yoko Irukayama-Tomobe; Yasuhiro Ogawa; Yukiko Ishikawa; Yurie Watanabe; Daichi Hayakawa; Hiroaki Gouda; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2017.07.011

Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

The essential structure of the orexin 1 receptor (OX₁R) antagonist YNT-707 (2) was clarified, particularly the roles to OX₁R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX₁R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX₁R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX₁R ligands.

Original language	English (US)
Pages (from-to)	4176-4179
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2017.07.011
State	Published - 2017

Keywords

4,5-Epoxy ring
Morphinan
Nalfurafine
Opioid
Orexin
YNT-707

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2017.07.011

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Yamamoto, N., Ohrui, S., Okada, T., Yata, M., Saitoh, T., Kutsumura, N., Nagumo, Y., Irukayama-Tomobe, Y., Ogawa, Y., Ishikawa, Y., Watanabe, Y., Hayakawa, D., Gouda, H., Yanagisawa, M., & Nagase, H. (2017). Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor. Bioorganic and Medicinal Chemistry Letters, 27(17), 4176-4179. https://doi.org/10.1016/j.bmcl.2017.07.011

Yamamoto, N, Ohrui, S, Okada, T, Yata, M, Saitoh, T, Kutsumura, N, Nagumo, Y, Irukayama-Tomobe, Y, Ogawa, Y, Ishikawa, Y, Watanabe, Y, Hayakawa, D, Gouda, H, Yanagisawa, M & Nagase, H 2017, 'Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor', Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 17, pp. 4176-4179. https://doi.org/10.1016/j.bmcl.2017.07.011

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title = "Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor",

abstract = "The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.",

keywords = "4,5-Epoxy ring, Morphinan, Nalfurafine, Opioid, Orexin, YNT-707",

author = "Naoshi Yamamoto and Sayaka Ohrui and Takahiro Okada and Masahiro Yata and Tsuyoshi Saitoh and Noriki Kutsumura and Yasuyuki Nagumo and Yoko Irukayama-Tomobe and Yasuhiro Ogawa and Yukiko Ishikawa and Yurie Watanabe and Daichi Hayakawa and Hiroaki Gouda and Masashi Yanagisawa and Hiroshi Nagase",

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year = "2017",

doi = "10.1016/j.bmcl.2017.07.011",

language = "English (US)",

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T1 - Essential structure of orexin 1 receptor antagonist YNT-707, Part I

T2 - Role of the 4,5-epoxy ring for binding with orexin 1 receptor

AU - Yamamoto, Naoshi

AU - Ohrui, Sayaka

AU - Okada, Takahiro

AU - Yata, Masahiro

AU - Saitoh, Tsuyoshi

AU - Kutsumura, Noriki

AU - Nagumo, Yasuyuki

AU - Irukayama-Tomobe, Yoko

AU - Ogawa, Yasuhiro

AU - Ishikawa, Yukiko

AU - Watanabe, Yurie

AU - Hayakawa, Daichi

AU - Gouda, Hiroaki

AU - Yanagisawa, Masashi

AU - Nagase, Hiroshi

PY - 2017

Y1 - 2017

N2 - The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.

AB - The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.

KW - 4,5-Epoxy ring

KW - Morphinan

KW - Nalfurafine

KW - Opioid

KW - Orexin

KW - YNT-707

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Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

Abstract

Keywords

ASJC Scopus subject areas

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