新型阿片受体部分激动剂－噻吩诺啡及其衍生物的构效关系研究

为了探讨新型阿片受体部分激动剂——噻吩诺啡药理作用的结构基础, 本研究在大鼠热辐射甩尾和小鼠热板致痛模型上, 评价了噻吩诺啡镇痛作用的强度与有效时间, 并通过其与一系列衍生物的相互比较, 分析该类化合物的构效关系。结果显示, 噻吩诺啡为强效、长效的阿片受体部分激动剂; N位上的环丙甲基决定了噻吩诺啡部分激动剂的特性; 改变噻吩环与侧链的连接位点对镇痛活性没有显著影响; 侧链中含有噻吩环的衍生物有效时间均较长, 用吡啶环、苯环替换侧链中的噻吩环, 使化合物的有效时间明显缩短, 提示噻吩环可能与长效作用密切相关。本研究为新结构类型的长效阿片化合物的开发提供了一些线索。

Structure-activity relationships analysis of thienorphine and its derivatives

Thienorphine is a chemically-new opioid developed in Beijing Institute of Pharmacology and Toxicology.  To elucidate the chemical basis for the unique pharmacological effects of thienorphine, 15 derivatives were synthesized according to combinatorial chemistry and the structure-activity relationships of these compounds were studied.  It is demonstrated that thienorphine is a potent long-acting partial agonist.  N-Cyclopropylmethyl is responsible for the antagonist effect of thienorphine.  More importantly, thiophene at the end of side chain is most likely the pharmacophore accounts for the long-lasting effect of thienorphine.  Change of the connection of thiophene and the side chain does not result in changes in the antinociceptive activity.