Riley T N, Bagley J R
J Med Chem. 1979 Oct;22(10):1167-71. doi: 10.1021/jm00196a004.
Relatively little information is available concerning the influence of conformational factors on the potent analgesic actions of the 4-anilidopiperidines. A series of N-substituted 3 alpha- and 3 beta-(propananilido)nortropanes have been designed, synthesized, and stereochemically characterized as semirigid analogues of the 4-anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. Conformational analysis of 3 alpha-propananilides (4) reveals a boat conformation for the preferred conformation of the piperidine ring of these tropane analogues. Evaluation of the analgesic potencies of the isomeric N-substituted 3-(propananilido)nortropanes of this study indicates greater potency for the 3 beta-(propananilido) isomers (5) with N-benzyl and N-phenethyl substitution as compared to the corresponding N-substituted 3 alpha-propananilides. Analysis of relative solubility differences among these isomers suggests that both structural and stereochemical influences predominate in affecting analgesic potency.
关于构象因素对4-苯胺基哌啶类强效镇痛作用的影响，目前可获得的信息相对较少。设计、合成了一系列N-取代的3α-和3β-（丙酰苯胺基）降托烷，并对其进行了立体化学表征，作为4-苯胺基哌啶类镇痛药的半刚性类似物，试图研究某些立体化学因素对这类化合物镇痛作用的影响。对3α-丙酰苯胺（4）的构象分析表明，这些托烷类似物哌啶环的优选构象为船式构象。本研究对异构N-取代的3-（丙酰苯胺基）降托烷的镇痛效力评估表明，与相应的N-取代3α-丙酰苯胺相比，具有N-苄基和N-苯乙基取代的3β-（丙酰苯胺基）异构体（5）效力更强。对这些异构体之间相对溶解度差异的分析表明，结构和立体化学影响在影响镇痛效力方面均占主导地位。
