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

作者：Nagase Hiroshi^*; Yamamoto Naoshi; Yata Masahiro; Ohrui Sayaka; Okada Takahiro; Saitoh Tsuyoshi; Kutsumura Noriki; Nagumo Yasuyuki; Irukayama Tomobe Yoko; Ishikawa Yukiko; Ogawa Yasuhiro; Hirayama Shigeto; Kuroda Daisuke; Watanabe Yurie; Gouda Hiroaki; Yanagisawa Masashi

来源：Journal of Medicinal Chemistry, 2017, 60(3): 1018-1040.

DOI：10.1021/acs.jmedchem.6b01418

Nalfurafine, a kappa-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.

• 出版日期2017-2-9