On the inhibition of muscle membrane chloride conductance by aromatic carboxylic acids
On the inhibition of muscle membrane chloride conductance by aromatic carboxylic acids
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芳香族羧酸对肌膜氯电导的抑制作用
DOI：
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发表时间：
1977
期刊：
影响因子：
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通讯作者：
R. Barchi
中科院分区：
文献类型：
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作者：
P. Palade;R. Barchi
在大鼠膈肌制备物中测试了作为苯甲酸类似物的25种芳族羧酸对氯离子电导（G（Cl））的影响。在25种中，19种显示出降低膜G（Cl），对其他膜参数的影响很小，尽管它们的表观K（i）变化很大。如果暴露时间不延长，这种抑制是可逆的。研究的最有效的类似物是蒽-9-COOH（9-AC; K（i）= 1.1 × 10（-5）M）。活性类似物产生的浓度依赖性抑制类型与在单个位点或具有相似结合亲和力的一组位点处的相互作用一致，尽管亲脂性和K（i）之间也显示出相关性。结构活性分析表明，疏水环取代通常增加抑制活性，而帕拉极性取代降低效力。这些化合物似乎不通过改变膜表面电荷来抑制G（Cl），并且产生的抑制不是电压依赖性的。Cl（-）电流的I-V关系的定性特征没有改变。所有阴离子的电导率并不均匀地改变这些酸，因为将预期从空间位阻的一个共同的通道。降低G（Cl）90%以上的9-AC浓度导致G（I）略有增加。在高水平的9-AC得到的完整的电导序列是在控制条件下得到的相反。渗透性序列随着9-AC浓度的增加而进行性变化，并最终在高水平的类似物下反转。芳香族羧酸似乎抑制G（Cl）通过结合到一个特定的膜内网站和改变膜阴离子通道的选择性序列。
25 aromatic carboxylic acids which are analogs of benzoic acid were tested in the rat diaphragm preparation for effects on chloride conductance (G(Cl)). Of the 25, 19 were shown to reduce membrane G(Cl) with little effect on other membrane parameters, although their apparent K(i) varied widely. This inhibition was reversible if exposure times were not prolonged. The most effective analog studied was anthracene-9-COOH (9-AC; K(i) = 1.1 x 10(-5) M). Active analogs produced concentration-dependent inhibition of a type consistent with interaction at a single site or group of sites having similar binding affinities, although a correlation could also be shown between lipophilicity and K(i). Structure-activity analysis indicated that hydrophobic ring substitution usually increased inhibitory activity while para polar substitutions reduced effectiveness. These compounds do not appear to inhibit G(Cl) by altering membrane surface charge and the inhibition produced is not voltage dependent. Qualitative characteristics of the I-V relationship for Cl(-) current are not altered. Conductance to all anions is not uniformly altered by these acids as would be expected from steric occlusion of a common channel. Concentrations of 9-AC reducing G(Cl) by more than 90 percent resulted in slight augmentation of G(I). The complete conductance sequence obtained at high levels of 9-AC was the reverse of that obtained under control conditions. Permeability sequences underwent progressive changes with increasing 9-AC concentration and ultimately inverted at high levels of the analog. Aromatic carboxylic acids appear to inhibit G(Cl) by binding to a specific intramembrane site and altering the selectivity sequence of the membrane anion channel.