Clinical applications of small-molecule GABAAR modulators for neurological disorders

Guangyong Chen; Meiling Xu; Zhuo Chen; Fuwei Yang

doi:10.1016/j.bioorg.2024.107983

Clinical applications of small-molecule GABA_AR modulators for neurological disorders

Bioorg Chem. 2024 Nov 22:153:107983. doi: 10.1016/j.bioorg.2024.107983. Online ahead of print.

Authors

Guangyong Chen¹, Meiling Xu², Zhuo Chen³, Fuwei Yang⁴

Affiliations

¹ Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China.
² Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China.
³ Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China. Electronic address: neurochen1984@jlu.edu.cn.
⁴ Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China. Electronic address: yfw@jlu.edu.cn.

PMID: 39581171
DOI: 10.1016/j.bioorg.2024.107983

Abstract

Gamma-aminobutyric acid type A receptor (GABA_AR) 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 GABA_AR modulators. Benzodiazepines, such as Diazepam, are well-known positive allosteric modulators (PAMs) that enhance GABA_AR 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 GABA_AR, reducing some of these side effects. Neurosteroids such as allopregnanolone and its synthetic analogs, including Brexanolone, have emerged as potent GABA_AR 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 GABA_AR 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 GABA_AR modulators with improved therapeutic outcomes.

Keywords: Clinical applications; Drugs; GABA(A)R modulators; Neurological disorders; Synthetic approaches.

Publication types

Review