Essential structure of orexin 1 receptor antagonist YNT-707: Conversion of the 16-cyclopropylmethyl group to the 16-sulfonamide group in D-nor-nalfurafine derivatives

Koki Katoh, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Tsuyoshi Saitoh, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journalArticlepeer-review

Abstract

The five-membered D-ring nalfurafine (D-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the D-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX1R) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OX1R. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated D-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the D-nor-nalfurafine derivatives had a greater effect on the affinities for the OX1R than did the 14- and 17-substituents of nalfurafine derivatives.

Original languageEnglish (US)
Article number128550
JournalBioorganic and Medicinal Chemistry Letters
Volume59
DOIs
StatePublished - Mar 1 2022
Externally publishedYes

Keywords

  • Antagonist
  • Morphinan
  • Nalfurafine
  • Orexin
  • Sulfonamide

ASJC Scopus subject areas

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

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