TY - JOUR
T1 - Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine
T2 - Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine
AU - Nagumo, Yasuyuki
AU - Katoh, Koki
AU - Iio, Keita
AU - Saitoh, Tsuyoshi
AU - Kutsumura, Noriki
AU - Yamamoto, Naoshi
AU - Ishikawa, Yukiko
AU - Irukayama-Tomobe, Yoko
AU - Ogawa, Yasuhiro
AU - Baba, Takeshi
AU - Tanimura, Ryuji
AU - Yanagisawa, Masashi
AU - Nagase, Hiroshi
N1 - Funding Information:
This work was supported by JSPS KAKENHI (20K05743 to T.S.; 16H05098 to H.N., Y.I-T., T.S.; 18K11014 to Y.I-T., T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 “LivinginSpace” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.), Japan Foundation for Applied Enzymology (16H007 to T.S.) and Toray Industries, Inc. IIIS is also supported by the World Premier International Research Center ( WPI ) Initiative, Japan. We thank Prof. Minoru Narita (Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences) for in vivo experimental supports.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - Aversion
KW - Nalfurafine
KW - Nalfurafine derivatives with 5 membered D-ring
KW - Orexin 1 receptor
KW - Sedation
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U2 - 10.1016/j.bmcl.2020.127360
DO - 10.1016/j.bmcl.2020.127360
M3 - Article
C2 - 32738987
AN - SCOPUS:85087211815
VL - 30
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 17
M1 - 127360
ER -