Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors

Article abstract of DOI:10.1016/j.bmc.2008.05.049

The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABA_A receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABA_A receptor, selected compounds were tested on the α₁β₂γ_2s, α₂β₂γ_2s and α₃β₂γ_2s GABA_A receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α₁- versus α₂- and α₃-containing receptors, and high-affinity ligands essentially selective for α₁ over α₃ were developed.