Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

Tsuyoshi Saitoh, Kazunori Seki, Ryo Nakajima, Naoshi Yamamoto, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, R. Tanimura, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - Jan 1 2019

Fingerprint

Morphinans
Orexin Receptors
Sulfonamides
Scaffolds
Amides
Skeleton
Ligands
Derivatives
4,5-epoxymorphinan
Orexin Receptor Antagonists

Keywords

  • Morphinan
  • Nalfurafine
  • Orexin
  • Ring removal
  • YNT-707

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 IV : The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity. / Saitoh, Tsuyoshi; Seki, Kazunori; Nakajima, Ryo; Yamamoto, Naoshi; Kutsumura, Noriki; Nagumo, Yasuyuki; Irukayama-Tomobe, Yoko; Ogawa, Yasuhiro; Ishikawa, Yukiko; Tanimura, R.; Yanagisawa, Masashi; Nagase, Hiroshi.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.

Research output: Contribution to journalArticle

Saitoh, Tsuyoshi ; Seki, Kazunori ; Nakajima, Ryo ; Yamamoto, Naoshi ; Kutsumura, Noriki ; Nagumo, Yasuyuki ; Irukayama-Tomobe, Yoko ; Ogawa, Yasuhiro ; Ishikawa, Yukiko ; Tanimura, R. ; Yanagisawa, Masashi ; Nagase, Hiroshi. / Essential structure of orexin 1 receptor antagonist YNT-707, Part IV : The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity. In: Bioorganic and Medicinal Chemistry Letters. 2019.
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AU - Yamamoto, Naoshi

AU - Kutsumura, Noriki

AU - Nagumo, Yasuyuki

AU - Irukayama-Tomobe, Yoko

AU - Ogawa, Yasuhiro

AU - Ishikawa, Yukiko

AU - Tanimura, R.

AU - Yanagisawa, Masashi

AU - Nagase, Hiroshi

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AB - The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

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