Ligand Binding and Functional Effect of Novel Bicyclic α5 GABA Receptor Negative Allosteric Modulators.

The significant importance of GABA receptors in the treatment of central nervous system (CNS) disorders has been known for a long time. However, only in recent years have experimental protein structures been published that can open the door to understanding protein-ligand interactions and may effectively help the rational drug design for the future. In our previous work (Szabó, G.

Novel imidazo[1,5-a]quinoxaline derivatives: SAR, selectivity and modeling challenges en route to the identification of an α5-GABAA receptor NAM.

Initial optimization of a series of novel imidazo[1,5-a]quinoxaline compounds originated from a heuristic approach combining two known structural moieties towards α5-GABA receptor is shown. This work reveals one-digit nanomolar active compounds as well as positive and negative allosteric modulators resulted from our exploratory approach. To deepen our understanding, their diverse mechanistic nature resulted from in silico modeling is also disclosed.

Identification of Triazolopyridines as Selective α5-GABA Receptor Negative Allosteric Modulators by a Hybridization Approach.

The identification and characterization of novel triazolopyridine derivatives with selective α5 subunit-containing GABA receptor negative allosteric modulator (NAM) activity are disclosed. As a result of screening of our corporate compound deck, we identified a moderately potent hit that was converted to an advanced hit bearing better physicochemical and pharmacological properties using a hybridization approach. Subsequent optimization led to the identification of potent and subtype-selective α5-GABA receptor NAMs representing a new chemotype in this area.