Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes.
Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes.
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抑制剂与兔肾刷状缘膜 TEA/H 交换器的结构和相互作用。
DOI：
10.1007/bf00374145
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Wunz,TP
中科院分区：
文献类型：
--
作者：
Wright,SH;Wunz,TM;Wunz,TP
有机阳离子（OC）的肾脏分泌涉及载体介导的OC在近端细胞的管腔膜中交换为H+。为了评估化学结构对潜在底物与此过程的相互作用的影响，我们研究了一系列季铵化合物对OC四乙基铵（TEA）在分离的肾刷状缘膜囊泡的制备中的转运的影响。表观抑制效力变化超过104倍，如抑制剂系数（KiTEA）所示，其近似值范围为0.5 μM至5 mM。TEA/H+交换的最差抑制剂是具有羧基或羟基残基的分子，而向母体分子添加亚甲基基团倾向于增加抑制效力。表观KiTEA与计算的辛醇：水分配系数（以相对亲脂性因子表示）的图显示这两个参数之间存在明显的相关性，尽管对于具有非常不同的母体结构的分子，表观亲脂性和KiTEA之间存在相当大的变异性。对于具有相似母体结构的选定分子组（例如，然后是四烷基铵或4-苯基吡啶鎓、3-苯基吡啶鎓和喹啉鎓化合物），计算的亲脂性与表观KiTEA之间的相关性更加明显。然而，即使在这些组的密切相关的母体结构，似乎是微妙的，但系统的，抑制效力的变化，可能已经与空间因素的影响，抑制剂的结合TEA/H+交换。我们的结论是，亲脂性的季铵化合物的结合，并随后抑制，管腔TEA/H+交换的主要因素。特定的空间因素可能会影响底物与交换剂的结合，但在这种相互作用中起次要作用。
The renal secretion of organic cations (OCs) involves a carrier-mediated exchange of OC for H+in the luminal membrane of proximal cells. To assess the influence of chemical structure on the interaction of potential substrates with this process we examined the effect of a series of quaternary ammonium compounds on the transport of the OC tetraethylammonium (TEA) in a preparation of isolated renal brush-border membrane vesicles. Apparent inhibitory potency varied over a factor of 104, as expressed in inhibitor coefficients (KiTEA) whose approximate values ranged from 0.5 μM to 5 mM. The poorest inhibitors of TEA/H+exchange were those molecules with carboxyl or hydroxyl residues, whereas the addition of methylene groups to a parent molecule tended to increase inhibitory potency. A plot of apparentKiTEAversus calculated octanol:water partition coefficient (expressed in terms of a relative lipophilicity factor) showed a clear correlation between these two parameters, although there was considerable variability between apparent lipophilicity andKiTEAfor molecules with very different parent structures. For select groups of molecules with similar parent structures (e.g., then-tetraalkylammoniums or the 4-phenylpyridinium, 3-phenylpyridinium, and quinolinium compounds) the correlation between calculated lipophilicity and apparentKiTEAwas more marked. However, even within these groups of closely related parent structures, there appeared to be subtle, but systematic, variations in inhibitory potency that may have been related to the influence of steric factors on the binding of inhibitors to the TEA/H+exchanger. We conclude that the lipophilic nature of a quaternary ammonium compound represents the predominant factor in the binding to, and subsequent inhibition of, luminal TEA/H+exchange. Specific steric factors may influence the binding of substrate to the exchanger, but play a secondary role in this interaction.