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

ABSTRACT: 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 α₄β₁δ 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 (IC₅₀ of 1.03 μM) was used for analogue search resulting in 018 (IC₅₀ 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

SUBMITTER: Falk-Petersen CB 

PROVIDER: S-EPMC7308271 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature