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 journalArticle

2 Citations (Scopus)

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 languageEnglish (US)
JournalBioorganic and Medicinal Chemistry
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Orexin Receptors
Morphinans
Derivatives
Amides
Assays
Orexin Receptor Antagonists

Keywords

  • Conformational analysis
  • Morphinan
  • Orexin
  • OX R antagonist

ASJC Scopus subject areas

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

Cite this

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; Saitoh, Tsuyoshi; Kutsumura, Noriki; Nagumo, Yasuyuki; Irukayama-Tomobe, Yoko; Ogawa, Yasuhiro; Ishikawa, Yukiko; Watanabe, Yurie; Hayakawa, Daichi; Gouda, Hiroaki; Yanagisawa, Masashi; Nagase, Hiroshi.

In: Bioorganic and Medicinal Chemistry, 01.01.2019.

Research output: Contribution to journalArticle

Yamamoto, Naoshi ; Ohrui, Sayaka ; Okada, Takahiro ; Saitoh, Tsuyoshi ; Kutsumura, Noriki ; Nagumo, Yasuyuki ; Irukayama-Tomobe, Yoko ; Ogawa, Yasuhiro ; Ishikawa, Yukiko ; Watanabe, Yurie ; Hayakawa, Daichi ; Gouda, Hiroaki ; Yanagisawa, Masashi ; Nagase, Hiroshi. / 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. In: Bioorganic and Medicinal Chemistry. 2019.
@article{4eac069c016a41b782ff1c9db7601c26,
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, Orexin, OX R antagonist",
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",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.bmc.2019.03.010",
language = "English (US)",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",

}

TY - JOUR

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

PY - 2019/1/1

Y1 - 2019/1/1

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 - Orexin

KW - OX R antagonist

UR - http://www.scopus.com/inward/record.url?scp=85062615110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062615110&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2019.03.010

DO - 10.1016/j.bmc.2019.03.010

M3 - Article

C2 - 30871861

AN - SCOPUS:85062615110

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

ER -