The GABAA Receptor as Target for Novel Heterocyclic Compounds

Abstract: Ligands for the benzodiazepine-binding site of the GABAA receptor can belong to structurally diverse classes of compounds including, in spite of the name of the binding site, many non-benzodiazepine structures. The GABAA receptor is a ligand-gated ion channel assembled of five subunits from eight different classes with multiple isoforms. The physiological effect elicited by benzodiazepines is believed to depend particularly on the isoform of the ?-subunit. In this study new heterocyclic ligands were designed and synthesized from a pharmacophore model of the benzodiazepine-binding site partly developed in this study. The novel heterocyclic benzodiazepine receptor ligands synthesized include 4-quinolones, aza flavones, triazoloquinazolines, isoxazoloquinolones, pyrazoloquinolones, isothiazoloquinolones and isothiazolyl amides. All of these compound classes were active in vitro on the GABAA receptor with the 4-quinolone 72 displaying the highest affinity (Ki = 0.048 nM) so far reported. The 4-quinolones and the aza flavones all displayed selectivity for ?1- versus ?2- and ?3-containing receptors, ranging from 2 to 27. The novel triazoloquinazoline and azoloquinolone scaffolds were designed de novo employing the pharmacophore model. A multigram-synthesis of the triazoloquinazoline 147 was developed and a library of ligands substituted on a position corresponding to the interface region was created. This study demonstrates the high predictive value of the developed benzodiazepine-binding site pharmacophore model and the utilization of de novo design of GABAA ligands. The hypothesis of the novel scaffolds, besides being potent, was they would allow for new substituent patterns in the benzodiazepine-binding site, and guided by molecular modelling, facilitate the development and understanding of GABAA subtype selective ligands.

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