Université de Nantes, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
CNRS, Neuro-PSI, UMR9197, 91191 Gif-Sur-Yvette, France; CEA/DRF/JOLIOT/SIMOPRO/Toxines Récepteur et Canaux Ioniques, F-91191 Gif-Sur-Yvette, France.
Bioorg Med Chem. 2019 Mar 1;27(5):700-707. doi: 10.1016/j.bmc.2019.01.013. Epub 2019 Jan 17.
In the field of nicotinic acetylcholine receptors (nAChRs), recognized as important therapeutic targets, much effort has been dedicated to the development of nicotinic analogues to agonize or antagonize distinct homo- and heteropentamers nAChR subtypes, selectively. In this work we developed di- and heptavalent nicotinic derivatives based on ethylene glycol (EG) and cyclodextrin cores, respectively. The compounds showed a concentration dependent inhibition of acetylcholine-induced currents on α7 nAChR expressed by Xenopus oocytes. Interesting features were observed with the divalent nicotinic derivatives, acting as antagonists with varied inhibitory concentrations (IC) in function of the spacer arm length. The best divalent compounds showed a 16-fold lowered IC compared to the monovalent reference (12 vs 195 µM). Docking investigations provide guidelines to rationalize these experimental findings.
在烟碱型乙酰胆碱受体（nAChRs）领域，这些受体被认为是重要的治疗靶点，研究人员致力于开发烟碱类似物，以选择性激动或拮抗不同的同源和异源五聚体 nAChR 亚型。在这项工作中，我们分别基于乙二醇（EG）和环糊精核心开发了二价和七价烟碱衍生物。这些化合物在表达于非洲爪蟾卵母细胞的α7 nAChR 上显示出浓度依赖性的乙酰胆碱诱导电流抑制作用。具有二价烟碱衍生物的有趣特征，其作为拮抗剂，其抑制浓度（IC）随间隔臂长度的变化而变化。与单价参考物（12 与 195 µM）相比，最佳的二价化合物的 IC 降低了 16 倍。对接研究为合理化这些实验结果提供了指导。
