Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABA sub(A) receptors

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 sub(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 alpha - and a gamma -subunit in the GABA sub(A) receptor, selected compounds were tested on the alpha sub(1) beta sub(2) gamma sub(2s), alpha sub(2) beta sub(2) gamma sub(2s) and alpha sub(3) beta sub(2) gamma sub(2s) GABA sub(A) receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for alpha sub(1)- versus alpha sub(2)- and alpha sub(3)-containing receptors, and high-affinity ligands essentially selective for alpha sub(1) over alpha sub(3) were developed.