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 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.