Variations on a scaffold - Novel GABAA receptor modulators.

Allosteric ligands of GABAA 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 GABAA 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 analyzed the structure-activity-relationship (SAR) of these novel ligands based on an azo-biaryl structural motif in α1β3 GABAA receptors, indicating interesting novel properties of the compound class.