Recent advances in GABAA receptor targeting ligands.

The γ-aminobutyric acid type A (GABAA) receptor is a principal mediator of fast inhibitory neurotransmission in the central nervous system. Dysfunction of the GABAA receptor (GABAAR) is closely associated with various neuropsychiatric disorders, making it a crucial target for developing therapeutic agents. Recent advances in cryo-electron microscopy (cryo-EM) have enabled direct visualization of subtype-specific conformations, ligand-binding pockets, and gating-associated structural rearrangements of GABAAR, providing a structural basis for mechanism-driven and subtype-selective allosteric modulator design. This review summarizes recent progress in GABAA receptor targeting ligands, with an emphasis on distinct allosteric binding sites, regulatory mechanisms, and subtype-dependent pharmacological profiles. Representative chemical scaffolds are discussed to illustrate structure-based optimization strategies and lead identification approaches informed by high-resolution structural data. Collectively, these advances highlight how structure-resolved insights are reshaping GABAAR drug discovery and enabling the development of next-generation therapeutics with improved efficacy and reduced adverse effects.