The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation–pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity.

中文翻译：

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α7 nAChR 的锍配体

α7 烟碱乙酰胆碱受体 (nAChR) 是一个重要的靶点，因为它在认知功能以及胆碱能抗炎途径中发挥着重要作用，其中有效稳定受体脱敏状态的配体尤其令人感兴趣。与良好脱敏剂相关的典型结构元件是铵药效团，但最近的工作已经确定带正电荷的锍形式的三价硫可以取代铵药效团中的氮。然而，使用锍基团的广度和范围在很大程度上尚未被探索。在这项工作中，我们调查了一组不同的锍化合物对 α7 以及其他 nAChR 亚型的功能活性。其中，我们发现诱导α7脱敏的能力范围广泛，其中4-羟基苯基二甲基锍和suplatast锍盐的脱敏作用最强。最小的锍化合物三甲基锍是 α7 和其他神经元 nAChR 的部分激动剂。与 α7 受体胞外结构域的分子对接揭示了除一种化合物之外的所有化合物在正位结合位点的首选位置，具有传统铵化合物所见的典型阳离子-π 相互作用。许多测试的化合物可以作为进一步开发 α7 脱敏能力和受体亚型选择性的有用平台。