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

• Published in: Bioorganic & medicinal chemistry letters 2020-09, Vol.30 (17), p.127360-127360, Article 127360
• Main Authors: Nagumo, Yasuyuki, Katoh, Koki, Iio, Keita, Saitoh, Tsuyoshi, Kutsumura, Noriki, Yamamoto, Naoshi, Ishikawa, Yukiko, Irukayama-Tomobe, Yoko, Ogawa, Yasuhiro, Baba, Takeshi, Tanimura, Ryuji, Yanagisawa, Masashi, Nagase, Hiroshi
• Format: Article
• Language: English
• Subjects: Aversion; Nalfurafine; Nalfurafine derivatives with 5 membered D-ring; Orexin 1 receptor; Sedation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127360

[Display omitted] 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.