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
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DOI：
10.1021/acs.jmedchem.6b01418
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发表时间：
2017-02-09
影响因子：
7.3
通讯作者：
Yanagisawa, Masashi
中科院分区：
文献类型：
--
作者：
Nagase, Hiroshi;Yamamoto, Naoshi;Yanagisawa, Masashi
Nalfurafine是一种κ-选择性阿片受体激动剂，意外地显示出对食欲素1受体（OX 1 R）的选择性拮抗剂活性（Ki = 250 nM）。将阿片样物质配体的17-氨基侧链修饰为芳基磺酰基，将6-呋喃丙烯酰胺链修饰为2-吡啶基丙烯酰胺，得到化合物71，其拮抗剂活性提高（OX 1 R，Ki = 1.36 nM; OX 2 R，无活性），对阿片样物质受体没有任何可检测的亲和力。71的二氢硫酸盐易溶于水，减弱吗啡的身体依赖性。此外，本研究中的所有活性纳呋拉芬衍生物对OX 2 R几乎没有活性，这导致了高OX 1 R选择性。这些结果表明，纳呋拉芬衍生物可能是一个有用的系列先导化合物，开发高选择性的OX 1 R拮抗剂。
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.