Clinical applications of small-molecule GABA A R modulators for neurological disorders.

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  • Author(s): Chen G;Chen G; Xu M; Xu M; Chen Z; Chen Z; Yang F; Yang F
  • Source:
    Bioorganic chemistry [Bioorg Chem] 2024 Dec; Vol. 153, pp. 107983. Date of Electronic Publication: 2024 Nov 22.
  • Publication Type:
    Journal Article; Review
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Amsterdam : Elsevier
      Original Publication: New York, London, Academic Press.
    • Subject Terms:
      Receptors, GABA-A*/metabolism ; Nervous System Diseases*/drug therapy ; Nervous System Diseases*/metabolism ; Small Molecule Libraries*/chemistry ; Small Molecule Libraries*/pharmacology ; Small Molecule Libraries*/therapeutic use; Humans ; Animals ; Molecular Structure ; GABA Modulators/pharmacology ; GABA Modulators/chemistry ; GABA Modulators/therapeutic use ; GABA Modulators/chemical synthesis
    • Abstract:
      Gamma-aminobutyric acid type A receptor (GABA A R) 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 A R modulators. Benzodiazepines, such as Diazepam, are well-known positive allosteric modulators (PAMs) that enhance GABA A R 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 A R, reducing some of these side effects. Neurosteroids such as allopregnanolone and its synthetic analogs, including Brexanolone, have emerged as potent GABA A R 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 A R 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 A R modulators with improved therapeutic outcomes.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Clinical applications; Drugs; GABA(A)R modulators; Neurological disorders; Synthetic approaches
    • Accession Number:
      0 (Receptors, GABA-A)
      0 (Small Molecule Libraries)
      0 (GABA Modulators)
    • Publication Date:
      Date Created: 20241124 Date Completed: 20241203 Latest Revision: 20241211
    • Publication Date:
      20241211
    • Accession Number:
      10.1016/j.bioorg.2024.107983
    • Accession Number:
      39581171