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

8 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",

author = "Naoshi Yamamoto and Sayaka Ohrui and Takahiro Okada 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",

note = "Funding Information: This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (B) Grant JP16H05098 (H.N., Y.I-T., T.S.), Grant-in-Aid for Early-Career Scientists Grant JP18K14352 (T.S.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas Grant JP15H05942 {\textquoteleft}{\textquoteleft}Living in Space”, Grant JP17H06049, JP18K11014), the Japan Foundation for Applied Enzymology Grant 16 T007, and Toray Industries, Inc. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan. We thank Professor Shuichi Hirono (Kitasato University) for generously allowing us to use “CAMDAS 2.1” program. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = apr,

day = "15",

doi = "10.1016/j.bmc.2019.03.010",

language = "English (US)",

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T1 - Essential structure of orexin 1 receptor antagonist YNT-707, part III

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

N1 - Funding Information: This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (B) Grant JP16H05098 (H.N., Y.I-T., T.S.), Grant-in-Aid for Early-Career Scientists Grant JP18K14352 (T.S.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas Grant JP15H05942 ‘‘Living in Space”, Grant JP17H06049, JP18K11014), the Japan Foundation for Applied Enzymology Grant 16 T007, and Toray Industries, Inc. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan. We thank Professor Shuichi Hirono (Kitasato University) for generously allowing us to use “CAMDAS 2.1” program. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/4/15

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

ASJC Scopus subject areas

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