Design, Synthesis, and Biological Evaluation of Imidazo[1,5-a]quinoline as Highly Potent Ligands of Central Benzodiazepine Receptors

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• 作者：Andrea Cappelli ; Maurizio Anzini ; Federica Castriconi ; Giorgio Grisci ; Marco Paolino ; Carlo Braile ; Salvatore Valenti ; Germano Giuliani ; Salvatore Vomero ; Angela Di Capua ; Laura Betti ; Gino Giannaccini ; Antonio Lucacchini ; Carla Ghelardini ; Lorenzo Di Cesare Mannelli ; Maria Frosini ; Lorenzo Ricci ; Gianluca Giorgi ; Maria Paola Mascia ; Giovanni Biggio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3353-3372
• 全文大小：847K
• 年卷期：0
• ISSN：1520-4804

文摘

A series of imidazo[1,5-a]quinoline derivatives was designed and synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high CBR affinity with K_i values within the submicromolar and subnanomolar ranges with interesting modulations in their structure–affinity relationships. In particular, fluoroderivative 7w (K_i = 0.44 nM) resulted in the most potent ligand among the imidazo[1,5-a]quinoline derivatives described so far. Overall, these observations confirmed the assumption concerning the presence of a large though apparently saturable lipophilic pocket in the CBR binding site region interacting with positions 4 and 5 of the imidazo[1,5-a]quinoline nucleus. The in vivo biological characterization revealed that compounds 7a,c,d,l,m,q,r,w show anxiolytic and antiamnestic activities without the unpleasant myorelaxant side effects of the classical 1,4-BDZ. Furthermore, the effect of 7l,q,r, and 8i in lowering lactate dehydrogenase (LDH) release induced by ischemia-like conditions in rat brain slices suggested neuroprotective properties for these imidazo[1,5-a]quinoline derivatives.