Kraszni Márta, Bányai István, Noszál Béla
Semmelweis University, Department of Pharmaceutical Chemistry, H-1092 Budapest, Högyes E. u. 9., Hungary.
J Med Chem. 2003 May 22;46(11):2241-5. doi: 10.1021/jm030767c.
The first conformer-specific experimental partition coefficients are presented for octanol/water, the most widespread solvent system to predict lipophilicity of drugs. Rotamer populations in octanol and water were elucidated from 1H NMR vicinal coupling constants and were combined with classical partition coefficients to obtain the conformer-specific ones. Feasibility of the determination of conformer-specific partition coefficients is exemplified on amphetamine and clenbuterol, two flexible drug molecules. Partition capacities of the amphetamine rotamers have been proven to be essentially equal. The conformers of clenbuterol, however, have been found to be greatly different in partition properties, which could be interpreted in terms of intramolecular interactions between the vicinal polar sites and the solvent-accessibility of the groups. The conformers could be put into order of their membrane-influx and -outflow propensities. Deviations between experimental and calculated log P values could also be interpreted in view of the species-specific partition coefficients.
首次给出了针对辛醇/水体系的特定构象体实验分配系数，辛醇/水是预测药物亲脂性最常用的溶剂体系。通过1H NMR邻位耦合常数阐明了辛醇和水中旋转异构体的丰度，并将其与经典分配系数相结合以获得特定构象体的分配系数。在苯丙胺和克伦特罗这两个柔性药物分子上例证了测定特定构象体分配系数的可行性。已证明苯丙胺旋转异构体的分配能力基本相等。然而，已发现克伦特罗的构象体在分配性质上有很大差异，这可以根据邻位极性位点之间的分子内相互作用以及基团的溶剂可及性来解释。这些构象体可以按照它们的膜流入和流出倾向进行排序。鉴于物种特异性分配系数，也可以解释实验和计算的log P值之间的偏差。
