Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory

The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [³⁵S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABA_A receptors. This effect was abolished in mice deficient in the GABA_A delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABA_A receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.