Waters J A
J Med Chem. 1978 Jul;21(7):628-33. doi: 10.1021/jm00205a007.
Aromatic carboxylic esters of 1-methyl-4-piperidinol were prepared and evaluated for analgesic activity. In addition, aralkyl, alkyl, and cycloalkyl carboxylates of the 4-piperidinol system and 3,4-dimethoxybenzoates of isomeric piperidinols (24-26) were synthesized. The 3,4-dimethoxybenzoate 23 was nearly twice as active as codeine in the mouse hot-plate assay. In monkeys, 23 showed no morphine-like physical dependence liability, cis- and trans-1,3-dimethyl-4-piperidinol esters 24 and 25 showed no binding to the opiate receptor in rat brain homogenates. The 3- and 4-monosubstituted and the 3,4-disubstituted benzoate esters were examined for qualitative structure-activity relationships with respect to parameters Esc and pi. Various structural features of this series of compounds that may have an affinity for receptor binding sites are discussed.
制备了1-甲基-4-哌啶醇的芳香羧酸酯并评估其镇痛活性。此外，还合成了4-哌啶醇体系的芳烷基、烷基和环烷基羧酸酯以及异构哌啶醇（24 - 26）的3,4-二甲氧基苯甲酸酯。在小鼠热板试验中，3,4-二甲氧基苯甲酸酯23的活性几乎是可待因的两倍。在猴子身上，23没有显示出吗啡样的身体依赖性倾向，顺式和反式-1,3-二甲基-4-哌啶醇酯24和25在大鼠脑匀浆中不与阿片受体结合。研究了3-和4-单取代以及3,4-二取代苯甲酸酯关于参数Esc和π的定性构效关系。讨论了该系列化合物可能对受体结合位点具有亲和力的各种结构特征。
