Effect of removal of the 14-hydroxy group on the affinity of the 4,5-epoxymorphinan derivatives for orexin and opioid receptors

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

Research output: Contribution to journalArticlepeer-review

Abstract

To investigate the contribution of hydrogen bonding between the 14-hydroxy group and the 6-amide chain on the binding affinity of nalfurafine toward KOR and OX1R, we prepared the 14-H and 14-dehydrated nalfurafine and their five-membered D-ring nalfurafine (D-nor-nalfurafine) derivatives. The 14-H and 14-dehydrated nalfurafine derivatives showed almost the same affinity for KOR as nalfurafine and more potent affinity for OX1R. On the other hand, 14-H and 14-dehydrated D-nor-nalfurafine derivatives showed weak affinity for KOR and almost no affinity for OX1R. The conformational analyses suggested that the 6-amide chains of the nalfurafine derivatives are mainly oriented just at or downward from the C-ring, while those of the D-nor-nalfurafine derivatives were mainly oriented toward the upper side of the C-ring even in the absence of the 14-hydroxy group. We postulated that the ion–dipole interaction between the 6-amide and the 16-nitrogen might stabilize the upwardly oriented 6-amide group. These results suggested that the 14-hydroxy group and the ion–dipole interaction would play important roles in the orientation of the 6-amide group, which might control the affinity between KOR and OX1R.

Original languageEnglish (US)
Article number128527
JournalBioorganic and Medicinal Chemistry Letters
Volume59
DOIs
StatePublished - Mar 1 2022
Externally publishedYes

Keywords

  • 14-H nalfurafine
  • 14-dehydration nalfurafine
  • D-nor-nalfurafine
  • KOR
  • Structure-activity relationship

ASJC Scopus subject areas

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

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