The Evolution of Benzodiazepine Allosteric Modulators: Structural Insights From Historical Milestones to Emerging Innovations in Drug Discovery and Development

Benzodiazepine drugs (BZDs) have been central to neuropsychopharmacology since the 1960s, acting as positive allosteric modulators of γ‐aminobutyric acid type A (GABA A ) receptors to enhance inhibitory neurotransmission. Despite their clinical efficacy, long‐term use is limited by tolerance, dependence, and cognitive side effects. This review summarizes the structural evolution of BZD modulators, with a focus on subtype‐selective interactions with GABA A receptor isoforms. Advances in cryo‐electron microscopy and AI‐driven modeling have clarified the architecture and pharmacological roles of distinct receptor subunits, enabling the design of ligands that dissociate therapeutic effects from adverse outcomes. We also highlight the development of nonclassical scaffolds—such as imidazopyridines, triazolopyridazines, and cinnolines—which improve metabolic stability and subtype specificity. In addition, emerging formulation technologies and novel indications, including chronic pain, asthma, and neurodegenerative disorders, broaden the therapeutic scope of BZD‐related compounds. Collectively, these advances underscore a shift toward rational, structure‐based design of next‐generation BZD receptor modulators with improved efficacy, safety, and clinical precision.