磺胺草醚、氟吡菌脲和新烟碱类药物对人类神经元α7烟碱乙酰胆碱受体的药理学和分子模型研究。

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY Toxicology and applied pharmacology Pub Date : 2024-10-10 DOI:10.1016/j.taap.2024.117123
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引用次数: 0

摘要

我们利用异源表达系统(爪蟾卵母细胞)进行了电生理学和分子对接研究,比较了四种新烟碱类(啶虫脒、吡虫啉、噻虫嗪和噻虫嗪)、一种亚磺酰亚胺(磺草酮)和一种丁烯内酯(氟吡嘧啶呋酮)对人类α7神经元烟碱乙酰胆碱受体(nAChRs)的影响。所有新烟碱类(噻虫嗪除外)以及最近推出的 nAChR 竞争性调节剂氟吡脲和磺胺草酮似乎都是比乙酰胆碱更弱的激动剂。在 α7 野生型中引入了 C 环的两个突变(E211N 和 E211P)和 D 环的一个突变(Q79K),已知这两个突变与新烟碱类药物的结合特性有关。有趣的是,人α7突变受体的乙酰胆碱和尼古丁诱导的活化没有改变,但对氯噻啶和吡虫啉的净电荷分别增强了。在 Q79K 突变的情况下,氟吡脲的反应强烈增加。分子对接研究表明,所考虑的配体的取向和相互作用与实验观察到的一致。具体来说,作为参考配体的乙酰胆碱和尼古丁的带电片段及其新烟碱同系物被发现被芳香残基包围,与 Trp171 和 Y210 有关键的相互作用。此外,分子对接研究还预测了尼古丁(以及大多数相应的新烟碱类药物片段)的乙酰胆碱羰基氧与吡啶环 Nsp2 氮以及 L141 主链 NH 之间由水介导的相互作用。对接得分在 6 kcal/mol 的很大范围内显示,与乙酰胆碱相比,大多数新烟碱类药物在 α7 nAChR 中的稳定性较差,磺草酮除外。
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Pharmacology and molecular modeling studies of sulfoxaflor, flupyradifurone and neonicotinoids on the human neuronal α7 nicotinic acetylcholine receptor
We conducted electrophysiological and molecular docking studies using a heterologous expression system (Xenopus oocytes) to compare the effects of four neonicotinoids (acetamiprid, imidacloprid, clothianidin and thiamethoxam), one sulfoximine, (sulfoxaflor), and one butenolide (flupyradifurone), on human α7 neuronal nicotinic acetylcholine receptors (nAChRs). All neonicotinoids (except thiamethoxam), as well as the recently introduced nAChR competitive modulators, flupyradifurone and sulfoxaflor, appear to be weaker agonists than acetylcholine. Two mutations in loop C (E211N and E211P) and one mutation in loop D (Q79K), known to be involved in the binding properties of neonicotinoids were introduced to the α7 wild type. Interestingly, the acetylcholine and nicotine-evoked activation was not modified in human α7 mutated receptors, but the net charge was enhanced for clothianidin and imidacloprid, respectively. Flupyradifurone responses strongly increased under the Q79K mutation. The molecular docking investigations demonstrated that the orientations and interactions of the ligands considered were in accordance with those observed experimentally. Specifically, the charged fragments of acetylcholine and nicotine, used as reference ligands, and their neonicotinoid homologs were found to be surrounded by aromatic residues, with key interactions with Trp171 and Y210. Furthermore, the molecular docking investigations predicted the water-mediated interaction between the carbonyl oxygen of acetylcholine and the Nsp2 nitrogen of the pyridine ring for nicotine (as well as for the majority of the corresponding neonicotinoid fragments) and main chain NH of L141. The docking scores, extending over a significant range of 6 kcal/mol, showed that most neonicotinoids were poorly stabilized in the α7 nAChR compared to acetylcholine, except sulfoxaflor.
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来源期刊
CiteScore
6.80
自引率
2.60%
发文量
309
审稿时长
32 days
期刊介绍: Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.
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