Cannon J G, Lee T M, Chang Y, Nyanda A M, Bhattacharyya B, Flynn J R, Chatterjee T, Bhatnagar R K, Long J P
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City 52242.
Pharm Res. 1988 Jun;5(6):359-64. doi: 10.1023/a:1015955527100.
In a continuing investigation of structural requirements for hemicholinium-like activity (inhibition of neuromuscular transmission due to inhibition of uptake of choline into nerve terminals), some additional molecular modifications of hemicholinium ("HC-3"; structure 1) were made. The target compounds were prepared by standard one- or two-step sequences. Noncyclic acetal moieties in general permitted retention of pharmacological activity, as did concomitant replacement of the central biphenyl "spacer" by other bulky cyclic groupings and replacement of the oxazinium rings by piperidine or 4-methylpiperidine. However, these modifications generally produced compounds of a lower potency. Replacement of the biphenyl moiety of HC-3 with polyakylene chains permitted retention of a considerable degree of activity. In these target compounds, the two quaternary nitrogens can exist the same distance apart (approximately 14 A) as in the hemicholinium molecule. The ditertiary amino congener of a pharmacologically active bis-quaternary oxazinium compound was almost completely inactive. To date, only one tertiary amine has been found which displays a significant degree of hemicholinium-like activity.
在对半胆碱样活性（因抑制胆碱摄取到神经末梢而抑制神经肌肉传递）的结构要求进行的持续研究中，对半胆碱（“HC - 3”；结构1）进行了一些额外的分子修饰。目标化合物通过标准的一步或两步合成序列制备。一般来说，非环状缩醛部分可保留药理活性，用其他庞大的环状基团取代中心联苯“间隔基”以及用哌啶或4 - 甲基哌啶取代恶嗪环也能保留药理活性。然而，这些修饰通常会产生效力较低的化合物。用聚亚烷基链取代HC - 3的联苯部分可保留相当程度的活性。在这些目标化合物中，两个季铵氮之间的距离可以与半胆碱分子中相同（约14埃）。一种具有药理活性的双季铵恶嗪化合物的二叔胺类似物几乎完全无活性。迄今为止，仅发现一种叔胺表现出显著程度的半胆碱样活性。
