TY - JOUR
T1 - Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies
AU - Nagase, Hiroshi
AU - Yamamoto, Naoshi
AU - Yata, Masahiro
AU - Ohrui, Sayaka
AU - Okada, Takahiro
AU - Saitoh, Tsuyoshi
AU - Kutsumura, Noriki
AU - Nagumo, Yasuyuki
AU - Irukayama-Tomobe, Yoko
AU - Ishikawa, Yukiko
AU - Ogawa, Yasuhiro
AU - Hirayama, Shigeto
AU - Kuroda, Daisuke
AU - Watanabe, Yurie
AU - Gouda, Hiroaki
AU - Yanagisawa, Masashi
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/2/9
Y1 - 2017/2/9
N2 - Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.
AB - Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.
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U2 - 10.1021/acs.jmedchem.6b01418
DO - 10.1021/acs.jmedchem.6b01418
M3 - Article
C2 - 28051300
AN - SCOPUS:85012177465
SN - 0022-2623
VL - 60
SP - 1018
EP - 1040
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -