Basmisanil, a highly selective GABA_A-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man.

ABSTRACT: GABA_A-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABA_A-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABA_A-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABA_A-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreove

SUBMITTER: Hipp JF 

PROVIDER: S-EPMC8032764 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature