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首页> 外文期刊>Life sciences >Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors.
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Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors.

机译：探测毒蕈碱型乙酰胆碱M2受体的变构位点内疏水结合袋的大小。

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摘要

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.
机译：已知含有侧邻苯二甲酰亚胺部分的己烷-双铵型化合物对毒蕈碱型M2受体的变构位点具有相当高的亲和力。为了更深入地了解侧向取代基对变构结合亲和力的贡献，合成了一系列具有单侧酰亚胺取代基的化合物，并测试了它们抑制变构抑制[3H] N-甲基东pol碱从受体蛋白解离的能力（对照t1 / 2 ＝ 2分钟; 3mM MgHCO 4，50mM Tris，pH 7.3，37℃）。在测试化合物中，含萘二甲酰亚胺的试剂（在ECs5处最大半衰期，diss = 60 nM）显示出最高的效价。显然，与含邻苯二甲酰亚胺的母体化合物W 84相比，它在NMS占据受体中对变构位点的亲和力高20倍。定量结构-活性关系的分析得出了侧基取代基的体积与变构能力之间的抛物线相关性。确定最大体积为约600A 3，这暗示变构结合位点包含酰亚胺部分的限定大小的结合袋。

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