Fischer Holger, Kansy Manfred, Avdeef Alex, Senner Frank
Pharmaceutical Research, Discovery Chemistry-Molecular Properties, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
Eur J Pharm Sci. 2007 May;31(1):32-42. doi: 10.1016/j.ejps.2007.02.001. Epub 2007 Feb 11.
The aim of this study was to investigate the permeation properties of 20 permanently positive charged molecules in the parallel artificial membrane permeability assay (PAMPA). Eight of them were derivatives of the N-alkyl-isoquinolinium salt and 12 were congeners of the dye rhodamine 110. Five out of 12 molecules from the rhodamine 110 series have one additional carboxylic group and two have two carboxylic acids. The experimentally derived effective permeability values (P(e)) cover a range of 3-4 log units. Ten compounds showed low permeabilities (P(e)<0.1x10(-6)cm/s), four medium permeabilities (0.1x10(-6)< or =P(e)<1x10(-6)cm/s) and six were highly permeable (P(e)> or =1x10(-6)cm/s). In addition, computational models were built with a number of calculated molecular descriptors and evaluated for their ability to predict membrane permeability. It turned out that the experimental P(e) values can be explained by electronic properties and parameters describing the shape of molecules. This work provides evidence that permanently charged molecules can have high passive membrane permeabilities provided that the charge can be spread over several aromatic ring systems.
本研究的目的是在平行人工膜通透性试验（PAMPA）中研究20种永久带正电荷分子的渗透特性。其中8种是N-烷基异喹啉鎓盐的衍生物，12种是罗丹明110染料的同系物。罗丹明110系列的12种分子中有5种带有一个额外的羧基，2种带有两个羧基。实验得出的有效渗透率值（P(e)）涵盖了3至4个对数单位的范围。10种化合物显示出低渗透率（P(e)<0.1x10(-6)cm/s），4种具有中等渗透率（0.1x10(-6)≤P(e)<1x10(-6)cm/s），6种具有高渗透率（P(e)≥1x10(-6)cm/s）。此外，利用一些计算得到的分子描述符建立了计算模型，并评估了它们预测膜通透性的能力。结果表明，实验得到的P(e)值可以通过描述分子形状的电子性质和参数来解释。这项工作提供了证据，即只要电荷能够分布在多个芳香环系统上，永久带电分子就可以具有较高的被动膜通透性。
