中氮茚类α7烟碱型乙酰胆碱受体激动剂的构效关系研究

The structure-activity relationships of novel α7 nicotinic acetylcholine receptor agonists based on indolizine scaffold

α7烟碱型乙酰胆碱受体(α7 nAChR)是一种配体门控型离子通道,在认知、学习和记忆方面具有关键作用,α7 nAChR功能下降与神经精神疾病认知障碍相关。本研究通过在中氮茚的不同位置引入多种类型的取代基,设计合成了一系列中氮茚类衍生物,并用双电极电压钳方法评价了化合物的激动活性。研究发现了16c(EC_(50)为1.60±0.19μmol·L^(-1),E_(max)为69.0%±2.8%)和17b(EC_(50)为2.74±0.74μmol·L^(-1),E_(max)为81.1%±9.3%)两个活性较高的化合物。构效关系研究表明,在中氮茚的6-位和8-位引入小的疏水基团分别能够提高化合物的效价和最大效应。

Alpha7 nicotinic acetylcholine receptor （α7 nAChR） is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships （SAR）. All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.600.19 μmolL-1 and maximum effect （Emax） of 69.0%2.8% compared with 3 mmolL-1 ACh. Compound 17b with 8-cyclopropyl substitution shows an increased Emax of 81.1%9.3% with EC50 at 2.740.74 μmolL-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.