Hasegawa T, Takagi K, Nadai M, Miyamoto K
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
J Pharm Sci. 1991 Apr;80(4):349-52. doi: 10.1002/jps.2600800413.
Binding of the bronchodilators N3-alkylxanthine and N3-alkyl-N1-methylxanthine derivatives to guinea pig serum albumin was investigated in vitro using the ultrafiltration method. A marked difference in the binding parameters of xanthine derivatives was observed, and binding was shown to be concentration dependent. Significant relations were observed among their binding parameter, dissociation constant (Kd), and hydrophobicity (log PC). The extent of binding of xanthine derivatives was increased both when a N3-methyl group was replaced by a longer alkyl chain and when a N3-alkylxanthine molecule was additionally replaced by a methyl group. Reversed-phase HPLC retention, as an index of hydrophobicity of xanthine derivatives, was also determined. Significant relationships were found between the adjusted retention time data for each xanthine derivative and their hydrophobicity or biological activities, such as their abilities to cause muscle relaxation and cyclic AMP phosphodiesterase (PDE) inhibition. These findings indicate that the difference in the extent of binding among xanthine derivatives is related to hydrophobicity, which is an important determinant of their biological activities.
采用超滤法在体外研究了支气管扩张剂N3-烷基黄嘌呤和N3-烷基-N1-甲基黄嘌呤衍生物与豚鼠血清白蛋白的结合情况。观察到黄嘌呤衍生物结合参数存在显著差异，且结合表现出浓度依赖性。在它们的结合参数、解离常数（Kd）和疏水性（log PC）之间观察到显著关系。当N3-甲基被更长的烷基链取代时，以及当N3-烷基黄嘌呤分子额外被一个甲基取代时，黄嘌呤衍生物的结合程度均增加。还测定了反相高效液相色谱保留时间，作为黄嘌呤衍生物疏水性的指标。发现每种黄嘌呤衍生物的调整保留时间数据与其疏水性或生物活性（如引起肌肉松弛的能力和环磷酸腺苷磷酸二酯酶（PDE）抑制能力）之间存在显著关系。这些发现表明，黄嘌呤衍生物结合程度的差异与疏水性有关，疏水性是其生物活性的一个重要决定因素。
