Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

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• 作者：Hiroshi NagaseNaoshi Yamamoto ; Masahiro Yata ; Sayaka Ohrui ; Takahiro Okada ; Tsuyoshi Saitoh ; Noriki Kutsumura ; Yasuyuki NagumoYoko Irukayama-Tomobe ; Yukiko Ishikawa ; Yasuhiro Ogawa ; Shigeto Hirayama ; Daisuke Kuroda ; Yurie Watanabe ; Hiroaki Gouda ; Masashi Yanagisawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：1018-1040
• 全文大小：968K
• ISSN：1520-4804

文摘

Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX₁R) (K_i = 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, K_i = 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.