Akamatsu M, Katayama T, Kishimoto D, Kurokawa Y, Shibata H, Ueno T, Fujita T
Department of Agricultural Chemistry, Kyoto University, Japan.
J Pharm Sci. 1994 Jul;83(7):1026-33. doi: 10.1002/jps.2600830720.
The partition coefficient (P) of neutral species and the apparent partition ratio (P') at pH 7 of the ionized form were measured with the 1-octanol/water system for a number of N-acetyl di- and tripeptide amides having un-ionizable and ionizable side chains. Their log values were studied in terms of free-energy-related substituent and substructural parameters using regression analysis to give correlation equations of high quality physicochemically as well as statistically. The intrinsic hydrophobicity of side-chain substituents and their steric effect on the relative solvation of the backbone CONH groups were significant in determining the log P values of the un-ionizable acetyl peptide amides. For the log P value of peptides with polar side-chain substituents, respective indicator variable terms were required to account for the sum of specific effects of substituents such as intramolecular hydrogen-bond formation and the "polar proximity factor" for augmentation of the hydrophobicity. For the log P'(pH 7) value of basic and acidic peptides, the ability of counterionic species to form ion-pairs, the change in the apparent hydrophobicity of ionizable groups from the intrinsic value for their nonionized forms, the effect of ion-pairing itself, and other effects were additionally considered. From the regression coefficients of the parameter terms in correlation equations an effective hydrophobicity index was defined for each side chain, and the application and its limitation were suggested.
使用1-辛醇/水体系，针对一系列具有不可电离和可电离侧链的N-乙酰二肽和三肽酰胺，测量了中性物种的分配系数（P）以及pH 7时离子化形式的表观分配比（P'）。利用回归分析，根据与自由能相关的取代基和亚结构参数研究了它们的对数，从而得出物理化学和统计学方面高质量的相关方程。侧链取代基的固有疏水性及其对主链CONH基团相对溶剂化的空间效应，在确定不可电离的乙酰肽酰胺的log P值时具有重要意义。对于具有极性侧链取代基的肽的log P值，需要各自的指示变量项来解释取代基的特定效应之和，如分子内氢键形成和增强疏水性的“极性接近因子”。对于碱性和酸性肽的log P'（pH 7）值，还额外考虑了抗衡离子形成离子对的能力、可电离基团从其非离子化形式的固有值起表观疏水性的变化、离子对本身的效应以及其他效应。根据相关方程中参数项的回归系数，为每个侧链定义了一个有效疏水性指数，并提出了其应用及其局限性。
