Darigabat and subtype-selective GABA-A modulation: pharmacology, clinical development, and translational challenges

INTRODUCTION: Darigabat is a selective γ-aminobutyric acid type A (GABA-A) receptor positive allosteric modulator targeting α2, α3, and α5 subunits, developed to preserve anxiolytic and anticonvulsant effects while reducing α1-mediated sedation and cognitive adverse events. Subtype-selective modulation represents a strategy to improve the safety of GABAergic therapies. AREAS COVERED: A literature search in PubMed, Embase, CENTRAL, and ClinicalTrials.gov up to June 2025 identified 20 preclinical and clinical studies. Darigabat demonstrated dose-proportional pharmacokinetics, high brain penetration, and overall acceptable tolerability, with dose-dependent central nervous system adverse effects at higher exposures. Preclinical models showed anticonvulsant and anxiolytic activity. However, clinical trials reported heterogeneous and inconsistent efficacy across indications. EXPERT OPINION: Darigabat supports the feasibility of subtype-selective GABA-A modulation. Early-phase studies in healthy volunteers suggested improved acute tolerability compared with nonselective benzodiazepines. In contrast, repeated-dose studies in patients revealed dose-dependent central nervous system adverse effects, including somnolence, psychomotor slowing, and cognitive impairment, indicating that α1-sparing reduces but does not eliminate these effects. Current evidence does not support a clear therapeutic role in chronic central nervous system disorders. Future research should focus on exposure-response relationships, identification of responsive subgroups, and biomarker integration. The ability to retain efficacy with improved safety remains uncertain.