van der Sluijs P, Meijer D K
J Pharmacol Exp Ther. 1985 Sep;234(3):703-7.
The interaction of eight mono- and four bisquaternary ammonium compounds with alpha-1 acid glycoprotein and its desialylated derivative was investigated. Protein binding was performed in vitro by equilibrium dialysis at 37 degrees C. The simple monoquaternary ammonium compounds tributylmethylammonium, tripropylmethylammonium, triethylmethylammonium and procainethobromide were not appreciably bound (unbound fraction greater than 0.99). Excellent negative correlations of unbound fraction and the log of the octanol/Krebs' partition coefficient were obtained for thiazinamium, N-methylimipramine, N-methyldeptropine and d-tubocurarine, both for alpha-1 acid glycoprotein (r = -0.99) and asialo alpha-1 acid glycoprotein (r = -0.94). Bisquaternary ammonium compounds, with the exception of hexafluorenium, were only poorly bound. Our binding data on N-methyl-deptropine, N-methylimipramine and thiazinamium reveal that these compounds are more avidly bound to alpha-1 acid glycoprotein than to albumin, in spite of their polar character. The interaction of N-methyldeptropine with alpha-1 acid glycoprotein was studied in more detail. Scatchard plots revealed the presence of two classes of binding sites. N-Methyldeptropine could effectively be displaced by imipramine from its high-affinity binding site. This points to the presence of a common high-affinity binding site for tertiary and quaternary ammonium compounds on alpha-1 acid glycoprotein.
研究了八种单季铵盐和四种双季铵盐化合物与α-1酸性糖蛋白及其去唾液酸化衍生物的相互作用。在37℃下通过平衡透析进行体外蛋白质结合实验。简单的单季铵盐化合物三丁基甲基铵、三丙基甲基铵、三乙基甲基铵和普鲁卡因托溴铵没有明显结合（未结合分数大于0.99）。噻嗪铵、N-甲基丙咪嗪、N-甲基去甲托品和d-筒箭毒碱的未结合分数与辛醇/克雷布斯分配系数的对数之间存在极好的负相关性，无论是对于α-1酸性糖蛋白（r = -0.99）还是去唾液酸α-1酸性糖蛋白（r = -0.94）。除六氟铵外，双季铵盐化合物的结合都很差。我们关于N-甲基去甲托品、N-甲基丙咪嗪和噻嗪铵的结合数据表明，尽管这些化合物具有极性，但它们与α-1酸性糖蛋白的结合比与白蛋白的结合更紧密。对N-甲基去甲托品与α-1酸性糖蛋白的相互作用进行了更详细的研究。Scatchard图显示存在两类结合位点。丙咪嗪可以有效地从其高亲和力结合位点取代N-甲基去甲托品。这表明在α-1酸性糖蛋白上存在一个叔铵盐和季铵盐化合物的共同高亲和力结合位点。
