Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine

Yasuyuki Nagumo, Koki Katoh, Keita Iio, Tsuyoshi Saitoh, Noriki Kutsumura, Naoshi Yamamoto, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Takeshi Baba, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase

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Abstract

The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OX1Rs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OX1R. The dual affinities of 1 for OX1R and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OX1R knockout mice, but not in wild-type mice. These results well support that OX1R suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.

Original languageEnglish (US)
Article number127360
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number17
DOIs
StatePublished - Sep 1 2020

Keywords

  • Aversion
  • Nalfurafine
  • Nalfurafine derivatives with 5 membered D-ring
  • Orexin 1 receptor
  • Sedation

ASJC Scopus subject areas

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

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