2. Academic Validation
  3. Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

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

  • J Med Chem. 2017 Feb 9;60(3):1018-1040. doi: 10.1021/acs.jmedchem.6b01418.
Hiroshi Nagase 1 2,  Naoshi Yamamoto 1,  Masahiro Yata 2,  Sayaka Ohrui 1,  Takahiro Okada 2,  Tsuyoshi Saitoh 1,  Noriki Kutsumura 1,  Yasuyuki Nagumo 1,  Yoko Irukayama-Tomobe 1,  Yukiko Ishikawa 1,  Yasuhiro Ogawa 1,  Shigeto Hirayama 3,  Daisuke Kuroda 4,  Yurie Watanabe 4,  Hiroaki Gouda 4,  Masashi Yanagisawa 1
Affiliations

Affiliations

  • 1 International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
  • 2 Graduate School of Pure and Applied Sciences, University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
  • 3 Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
  • 4 School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
PMID: 28051300 DOI: 10.1021/acs.jmedchem.6b01418
Abstract

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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