Clinical applications of small-molecule GABAR modulators for neurological disorders.

Gamma-aminobutyric acid type A receptor (GABAR) modulators are crucial in treating neurological and psychiatric disorders, including epilepsy, anxiety, insomnia, and depression. This review examines the synthetic approaches and clinical applications of representative small-molecule GABAR modulators. Benzodiazepines, such as Diazepam, are well-known positive allosteric modulators (PAMs) that enhance GABAR function, providing therapeutic effects but also associated with side effects like sedation and dependence. Non-benzodiazepine modulators, including Z-drugs like Zolpidem and Zaleplon, offer improved selectivity for the α1 subunit of GABAR, reducing some of these side effects. Neurosteroids such as allopregnanolone and its synthetic analogs, including Brexanolone, have emerged as potent GABAR modulators with applications in conditions like postpartum depression and refractory epilepsy. Advances in molecular biology and pharmacology have facilitated the development of isoform-specific modulators, potentially reducing off-target effects and enhancing therapeutic profiles. Additionally, combining GABAR modulators with other therapeutic agents has shown promise in enhancing efficacy and minimizing side effects. This review highlights the design strategies, pharmacodynamics, clinical efficacy, and safety profiles of these compounds, emphasizing the opportunities for developing novel GABAR modulators with improved therapeutic outcomes.