14β-O-Cinnamoylnaltrexone and Related Dihydrocodeinones are Mu Opioid Receptor Partial Agonists with Predominant Antagonist Activity
14β-O-Cinnamoylnaltrexone and Related Dihydrocodeinones are Mu Opioid Receptor Partial Agonists with Predominant Antagonist Activity
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DOI：
10.1021/jm8012272
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发表时间：
2009-03-26
影响因子：
7.3
通讯作者：
Husbands, S. M.
中科院分区：
文献类型：
--
作者：
Moynihan, H.;Jales, A. R.;Husbands, S. M.
合成纳曲酮14- o -肉桂酯(6)，并在离体组织实验和小鼠体内抗伤性实验中进行评价。其主要的阿片受体活性是拮抗mu受体（MOR），但未取代的肉桂酰衍生物（6a）在体外和体内均具有部分MOR激动剂活性。与等效的14-肉桂酰氨基吗啡酮(5)相比，肉桂酰氧基吗啡酮(6)作为MOR拮抗剂的作用时间较短，作为假不可逆拮抗剂的效果较差。肉桂酰氧可待因酮的抗伤性活性(7)并不显著高于吗啡酮(6)，但它们没有显示出任何伪不可逆的MOR拮抗作用。在这两个方面，这些特征不同于等效的14-肉桂酰氨基可待因酮(4)。
14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism, but the unsubstituted cinnamoyl derivative (6a) had partial MOR agonist activity in vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5), the cinnamoyloxy morphinones (6) as MOR antagonists had a shorter duration of action and were less effective as pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not significantly greater than that of the morphinones (6), but they exhibited no evidence of any pseudo irreversible MOR antagonism. In both respects, these profiles differed from those of the equivalent 14-cinnamoylaminocodeinones (4).