Variations on a scaffold - Novel GABAA receptor modulators

Abstract Allosteric ligands of GABA A receptors exist in many different chemotypes owing to their great usefulness as therapeutics, with benzodiazepines being among the best known examples. Many allosteric binding sites have been described, among them a site at the extracellular interface between the alpha principal face and the beta complementary face (α+/β-). Pyrazoloquinolinones have been shown to bind at α+/β-binding sites of GABA A receptors, exerting chiefly positive allosteric modulation at this location. In order to further explore molecular determinants of this type of allosteric modulation, we synthesized a library of ligands based on the PQ pharmacophore employing a ring-chain bioisosteric approach. In this study we analysed the structure-activity-relationship (SAR) of these novel ligands based on an azo-biaryl structural motif in α1β3 GABA A receptors, indicating interesting novel properties of the compound class.