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

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 Ki values within the submicromolar and subnanomolar ranges with interesting modulations in their structure–affinity relationships. In particular, fluoroderivative 7w (Ki = 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.