10.1021/jm058057p.s001 Erik Lager Erik Lager Pierre Andersson Pierre Andersson Jakob Nilsson Jakob Nilsson Ingrid Pettersson Ingrid Pettersson Elsebet Østergaard Nielsen Elsebet Østergaard Nielsen Mogens Nielsen Mogens Nielsen Olov Sterner Olov Sterner Tommy Liljefors Tommy Liljefors 4-Quinolone Derivatives:  High-Affinity Ligands at the Benzodiazepine Site of Brain GABA<sub>A</sub> Receptors. Synthesis, Pharmacology, and Pharmacophore Modeling American Chemical Society 2006 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 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/4_Quinolone_Derivatives_High_Affinity_Ligands_at_the_Benzodiazepine_Site_of_Brain_GABA_sub_A_sub_Receptors_Synthesis_Pharmacology_and_Pharmacophore_Modeling/3226255 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.