Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies.
Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies.
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6-甘氨酸取代的 14-苯基丙氧基吗啡喃的合成和药理活性，一类具有高阿片受体亲和力和抗伤害作用的新型阿片类药物。
DOI：
10.1021/jm101211p
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发表时间：
2011
影响因子：
7.3
通讯作者：
Schmidhammer,Helmut
中科院分区：
文献类型：
--
作者：
Spetea,Mariana;Windisch,Petra;Guo,Yan;Bileviciute-Ljungar,Indre;Schütz,Johannes;Asim,MuhammadFaheem;Berzetei-Gurske,IlonaP;Riba,Pal;Kiraly,Kornel;Fürst,Susanna;Al-Khrasani,Mahmoud;Schmidhammer,Helmut
本文报道了N-甲基吗啡喃和N-环丙基甲基吗啡喃中6-甘氨酸和14-苯丙氧基取代的合成及其对生物活性的影响。结合研究显示，所有新的14-苯基丙氧基吗啡烷（11−18）都显示出对阿片受体的高亲和力。用苯基丙氧基取代14-甲氧基导致对所有三种阿片受体类型的亲和力增强，δ和κ活性最显著增加，因此导致μ受体选择性丧失。所有化合物（11 - 18）在大鼠皮下给药后的甩尾试验中均显示出有效且持久的抗伤害感受作用。对于N-甲基衍生物13和14，镇痛效力分别在其14-甲氧基类似物9和10的范围内。甚至具有N-环丙基甲基取代基的衍生物15 - 18也可作为有效的抗伤害剂，其效力是吗啡的几倍。化合物13和14的皮下给药对角叉菜胶诱导的大鼠炎性痛敏产生显著和延长的通过外周阿片机制介导的镇痛作用。
The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions inN-methyl- andN-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11−18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of μ receptor selectivity. All compounds (11−18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For theN-methyl derivatives13and14, analgesic potencies were in the range of their 14-methoxy analogues9and10, respectively. Even derivatives15−18with anN-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds13and14produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.