Lager, Erik Andersson, Pierre Nilsson, Jakob Pettersson, Ingrid Nielsen, Elsebet Østergaard Nielsen, Mogens Sterner, Olov Liljefors, Tommy 4-Quinolone Derivatives:  High-Affinity Ligands at the Benzodiazepine Site of Brain GABA<sub>A</sub> Receptors. Synthesis, Pharmacology, and Pharmacophore Modeling The 3-ethoxycarbonyl-4-quinolone compound <b>1</b> has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA<sub>A</sub> receptors (Kahnberg et al. <i>J. Mol. Graphics Modelling </i><b>2004</b>, <i>23</i>, 253−261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds <b>20</b> and <b>23</b>−<b>25 </b>displaying sub-nanomolar affinities. A few of the compounds have been tested on the α<sub>1</sub>β<sub>2</sub>γ<sub>2S</sub> and α<sub>3</sub>β<sub>2</sub>γ<sub>2S</sub> GABA<sub>A</sub> receptor subtypes, and two of the compounds (<b>5</b> and <b>19</b>) display selectivity for α<sub>1</sub>- versus α<sub>3</sub>-containing receptors by a factor of 22 and 27, respectively. This selectivity for α<sub>1</sub>β<sub>2</sub>γ<sub>2S</sub> is in the same range as that for the well-known α<sub>1</sub> subunit selective compound zolpidem. α 1 subunit;receptor;α 1 β 2 γ 2 S;compound;graphics Modelling 2004;benzodiazepine site;α 3 β 2 γ 2 S GABA 2006-04-20
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10.1021/jm058057p.s001