Structural determinants of opioid activity in derivatives of 14-aminomorphinones:: Effects of changes to the chain linking of the C14-amino group to the aryl ring
Structural determinants of opioid activity in derivatives of 14-aminomorphinones:: Effects of changes to the chain linking of the C14-amino group to the aryl ring
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DOI：
10.1021/jm060595u
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发表时间：
2006-10-05
影响因子：
7.3
通讯作者：
Husbands, Stephen M.
中科院分区：
文献类型：
--
作者：
Rennison, David;Moynihan, Humphrey;Husbands, Stephen M.
14-氨基二氢吗啡酮和可待因酮系列阿片类配体已经产生了许多令人感兴趣的配体。为了研究14-取代基的重要性，制备了一系列侧链长度不同且酰胺和烯烃官能团减少的类似物。结合亲和力，尤其是 mu-阿片受体 (MOR) 的结合亲和力，很大程度上取决于侧链的芳香基团。在 [S-35] GTP gamma S 功能测定中，具有三碳侧链的配体比其较长链的对应物是更有效的拮抗剂，而较短的二碳链类似物具有更高的 MOR 功效，这一作用已在体内得到证实。在该系列中观察到耐洗结合，并且似乎与侧链长度无关。
The 14-aminodihydromorphinone and codeinone series of opioid ligands have produced a number of ligands of substantial interest. To investigate the importance of the 14-substituent, a series of analogues in which the side chain length is varied and the amide and alkene functions are reduced have been prepared. Binding affinity, particularly at the mu-opioid receptor (MOR), was largely determined by the aromatic group of the side chain. In the [S-35] GTP gamma S functional assay, the ligands having a three-carbon side chain were more potent antagonists than their longer chain counterparts, while shorter, two-carbon chain analogues were of higher MOR efficacy, an effect that was confirmed in vivo. Wash-resistant binding was observed within this series and appeared to be unrelated to side-chain length.