Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring

Naoshi Yamamoto; Sayaka Ohrui; Takahiro Okada; 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.bmc.2019.03.010

Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring

Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, 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

9 Scopus citations

Abstract

Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX ₁ R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX ₁ R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX ₁ R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

Original language	English (US)
Pages (from-to)	1747-1758
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	27
Issue number	8
DOIs	https://doi.org/10.1016/j.bmc.2019.03.010
State	Published - Apr 15 2019
Externally published	Yes

Keywords

Conformational analysis
Morphinan
OX R antagonist
Orexin

ASJC Scopus subject areas

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

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Yamamoto, N., Ohrui, S., Okada, T., Saitoh, T., Kutsumura, N., Nagumo, Y., Irukayama-Tomobe, Y., Ogawa, Y., Ishikawa, Y., Watanabe, Y., Hayakawa, D., Gouda, H., Yanagisawa, M., & Nagase, H. (2019). Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring. Bioorganic and Medicinal Chemistry, 27(8), 1747-1758. https://doi.org/10.1016/j.bmc.2019.03.010

Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring. / Yamamoto, Naoshi; Ohrui, Sayaka; Okada, Takahiro et al.
In: Bioorganic and Medicinal Chemistry, Vol. 27, No. 8, 15.04.2019, p. 1747-1758.

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

Yamamoto, N, Ohrui, S, Okada, T, Saitoh, T, Kutsumura, N, Nagumo, Y, Irukayama-Tomobe, Y, Ogawa, Y, Ishikawa, Y, Watanabe, Y, Hayakawa, D, Gouda, H, Yanagisawa, M & Nagase, H 2019, 'Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring', Bioorganic and Medicinal Chemistry, vol. 27, no. 8, pp. 1747-1758. https://doi.org/10.1016/j.bmc.2019.03.010

Yamamoto N, Ohrui S, Okada T, Saitoh T, Kutsumura N, Nagumo Y et al. Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring. Bioorganic and Medicinal Chemistry. 2019 Apr 15;27(8):1747-1758. doi: 10.1016/j.bmc.2019.03.010

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title = "Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring",

abstract = " Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX 1 R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX 1 R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX 1 R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.",

keywords = "Conformational analysis, Morphinan, OX R antagonist, Orexin",

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T2 - Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring

AU - Yamamoto, Naoshi

AU - Ohrui, Sayaka

AU - Okada, Takahiro

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

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Y1 - 2019/4/15

N2 - Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX 1 R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX 1 R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX 1 R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

AB - Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX 1 R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX 1 R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX 1 R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

KW - Conformational analysis

KW - Morphinan

KW - OX R antagonist

KW - Orexin

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Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring

Abstract

Keywords

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