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Brain GABA Α  receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α 4 β 1 δ GABA Α  receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABA Α  receptors. The initial screening hit  2027  (IC 50  of 1.03 μM) was used for analogue search resulting in  018  (IC 50  of 0.088 μM).  018  was most potent at α 3,4,5 -subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of  018  at recombinant human α 4 β 1 δ receptors and displacement of [ 3 H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of  018  was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that  2027  and  018  do not cross membranes, thus making the compounds less attractive for studying central GABA Α  receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABA Α  receptor-mediated effects of GABA e.g. in the immune system.

Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors