Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors.
Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors.
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DOI：
10.1021/jm060469q
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发表时间：
2006-07
影响因子：
7.3
通讯作者：
D. Sikazwe;M. Bondarev;M. Dukat;J. B. Rangisetty;B. Roth;R. Glennon
中科院分区：
文献类型：
--
作者：
D. Sikazwe;M. Bondarev;M. Dukat;J. B. Rangisetty;B. Roth;R. Glennon
各种含磺酰的化合物（如磺酰胺、砜）与人类5-HT6 5-羟色胺受体结合，但很难将这些药物的结合模式彼此联系起来，即使许多药物具有共同的SO2片段，也很难确定一个共同的药效团模型。基于麦角碱型构象可能对某些含磺胺的芳基烷基胺的结合很重要的假设，我们制备了一系列化合物，包括苯乙胺6、吡罗乙胺7和苯哌嗪9，用于h5-HT6受体的检测。结果（Ki值范围从大约1 nM到1000 nM）表明，这些药物中的许多可能以相关的方式结合，结构亲和力研究表明，苯乙胺和苯哌嗪类似物的苯磺酰胺部分可以“逆转”，缩写为砜，并移动到相邻位置，对亲和力的影响相对较小。尽管苯磺酰胺（或相关芳基磺酰胺）基团可能是各种5-HT6配体所共有的，但即使在相同的芳基烷基胺结构框架内，关于磺酰胺部分的具体构成和位置似乎也存在一定的纬度。提出了一个药效团模型来解释当前的一些发现。
Various sulfonyl-containing compounds (e.g. sulfonamides, sulfones) bind at human 5-HT6 serotonin receptors, but it has been difficult relating the binding mode(s) of such agents to one another, even though many possess a common SO2 moiety, to identify a common pharmacophore model(s). On the basis of the hypothesis that an ergoline-type conformation might be important for the binding of some sulfonamide-containing arylalkylamines, we prepared for examination at h5-HT6 receptors a series of compounds, including phenylethylamines 6, pyrroloethylamine 7, and phenylpiperazines 9. The results (with Ki values ranging from about 1 nM to >1000 nM) suggest that many of these agents likely bind in a related fashion, and structure-affinity studies indicate that the benzenesulfonamide portion of the phenylethylamine and phenylpiperazine analogues can be "reversed", abbreviated to a sulfone, and moved to an adjacent position with relatively little impact on affinity. Although a benzenesulfonamide (or related arylsulfonamide) group might be common to various 5-HT6 ligands, there appears to be some latitude with regard to the specific constitution and location of the sulfonamide moiety even within the same arylalkylamine structural framework. A pharmacophore model is presented to account for some of the current findings.