Selective Modulation of α5 GABA_A Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in <i>APP</i> Mouse Model of Alzheimer's Disease.

ABSTRACT: Selective negative allosteric modulators (NAMs), targeting α5 subunit-containing GABA_A receptors (GABA_ARs) as potential therapeutic targets for disorders associated with cognitive deficits, including Alzheimer's disease (AD), continually fail clinical trials. We investigated whether this was due to the change in the expression of α5 GABA_ARs, consequently altering synaptic function during AD pathogenesis. Using medicinal chemistry and computational modeling, we developed aqueous soluble hybrids of 6,6-dimethyl-3-(2-hydroxyethyl) thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophene-4(5H)-one, that demonstrated selective binding and high negative allosteric modulation, specifically for the α5 GABA_AR subtypes in constructed HEK293 stable cell-lines. Us

SUBMITTER: Petrache AL 

PROVIDER: S-EPMC7686552 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature