发现具有苯二氮䓬结合位点的 GABA A 受体相互作用的抗焦虑 2-二茂铁基-1,3-噻唑烷-4-酮。

Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site.

机构信息

Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia.

Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.

出版信息

Eur J Med Chem. 2014 Aug 18;83:57-73. doi: 10.1016/j.ejmech.2014.05.062. Epub 2014 May 28.

DOI:10.1016/j.ejmech.2014.05.062

PMID:24950490

Abstract

Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect.

摘要

本文报道了一系列 N-取代的 2-二茂铁基-1,3-噻唑烷-4-酮的合成、光谱、晶体学和电化学性质，这些化合物被设计为新型 GABA A 苯二氮䓬结合位点配体。标题化合物的抗焦虑性质在几种不同的体内模型中进行了评估，而最有效化合物 2-二茂铁基-3-(4-甲氧基苯乙基)-1,3-噻唑烷-4-酮的活性涉及 GABA A 受体复合物，这是从与已知 GABA A 靶向药物的实验中推断出来的。配体对接实验表明，新型化合物具有高剂量依赖性的抗焦虑活性，可能是由于它们与 GABA A 受体复合物的苯二氮䓬结合位点的有利相互作用。二茂铁核的引入以及噻唑烷酮核心和附加芳环之间距离的精细调整被认为是观察到的抗焦虑作用的关键结构要求。