Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors

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• 作者：Rosaria Gitto ; Laura De Luca ; Stefania Ferro ; Emilio Russo ; Giovambattista De Sarro ; Mariangela Chisari ; Lucia Ciranna ; Julio Alvarez-Builla ; Ramon Alajarin ; Maria Rosa Buemi ; Alba Chimirri
• 关键词：Glutamate ; GluN2B ; Indoles ; Ifenprodil ; Molecular docking
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 February, 2014
• 年：2014
• 卷：22
• 期：3
• 页码：1040-1048
• 全文大小：892 K

文摘

A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [³H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC₅₀ = 5.5 nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50 nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 鈥榙ual target鈥?neuroprotective agents.