Trummlitz G, Schmidt G, Wagner H U, Luger P
Arzneimittelforschung. 1984;34(8):849-59.
The crystal structures of the antiulcer drug 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one dihydrochloride (pirenzepine dihydrochloride, L-S 519 CL 2, Gastrozepin) and its monoprotonated form (pirenzepine monohydrochloride, L-S 519 CL) were determined by X-ray analysis. Molecular mechanics (MMPI) and semiempirical quantum chemical (MNDO) calculations showed that the calculated minimum energy conformations of the tricycle and of the exocyclic amide group are in agreement with the crystal structures. The conformational energies of pirenzepine as a function of four important torsional angles were calculated using different semiempirical quantum chemical methods with the CNDO/2 (complete neglect of differential overlap)-, MNDO (modified neglect of diatomic overlap)- and PCILO (perturbative configuration interaction using localized orbitals)-approximations. The conformation of one local energy minimum corresponds closely to the crystal structure of pirenzepine monohydrochloride. This conformation has a spatial arrangement which is analogous to a single consistent conformation known from the literature of 24 anticholinergic agents determined from their crystal structures by a computer graphics analysis. On the other hand there are no structural relationships of any low energy conformation of pirenzepine to conformations of other classes of tricyclic compounds which could rationalize their antidepressant, neuroleptic or antihistaminic activity. This finding explains the absence of any central effect of pirenzepine following intracerebral application. The computational elucidation of the conformational requirements for the interaction with the muscarinic receptors may be helpful for the interpretation of the selectivity of pirenzepine within the muscarinic system.
通过X射线分析确定了抗溃疡药物5,11 - 二氢 - 11 - [(4 - 甲基 - 1 - 哌嗪基)乙酰基] - 6H - 吡啶并[2,3 - b][1,4]苯并二氮杂䓬 - 6 - 酮二盐酸盐（哌仑西平二盐酸盐，L - S 519 CL 2，胃疡平）及其单质子化形式（哌仑西平一盐酸盐，L - S 519 CL）的晶体结构。分子力学（MMPI）和半经验量子化学（MNDO）计算表明，三环和环外酰胺基团的计算最低能量构象与晶体结构一致。使用不同的半经验量子化学方法，采用CNDO/2（完全忽略微分重叠）、MNDO（改进的忽略双原子重叠）和PCILO（使用定域轨道的微扰构型相互作用）近似，计算了哌仑西平作为四个重要扭转角函数的构象能。一个局部能量最小值的构象与哌仑西平一盐酸盐的晶体结构密切对应。这种构象具有一种空间排列，类似于通过计算机图形分析从其晶体结构确定的24种抗胆碱能药物文献中已知的单一一致构象。另一方面，哌仑西平的任何低能量构象与其他类三环化合物的构象之间没有结构关系，这些三环化合物的构象可以解释它们的抗抑郁、抗精神病或抗组胺活性。这一发现解释了脑内应用后哌仑西平没有任何中枢效应的原因。对与毒蕈碱受体相互作用的构象要求进行计算阐明，可能有助于解释哌仑西平在毒蕈碱系统内的选择性。
