4-Quinolone Derivatives:  High-Affinity Ligands at the Benzodiazepine Site of Brain GABA_A Receptors. Synthesis, Pharmacology, and Pharmacophore Modeling

The 3-ethoxycarbonyl-4-quinolone compound 1 has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA_A receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253−261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23−25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the α₁β₂γ_2S and α₃β₂γ_2S GABA_A receptor subtypes, and two of the compounds (5 and 19) display selectivity for α₁- versus α₃-containing receptors by a factor of 22 and 27, respectively. This selectivity for α₁β₂γ_2S is in the same range as that for the well-known α₁ subunit selective compound zolpidem.