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引用次数: 0
摘要
γ-氨基丁酸 A 型受体（GABAAR）调节剂是治疗癫痫、焦虑、失眠和抑郁等神经和精神疾病的关键。本综述探讨了具有代表性的小分子 GABAAR 调节剂的合成方法和临床应用。苯二氮卓类药物（如地西泮）是众所周知的正性异位调节剂（PAMs），可增强 GABAAR 的功能，提供治疗效果，但也有镇静和依赖性等副作用。非苯二氮卓调节剂，包括唑吡坦和扎来普隆等 Z 类药物，对 GABAAR 的 α1 亚基具有更好的选择性，从而减少了部分副作用。神经类固醇（如异孕烷酮及其合成类似物，包括 Brexanolone）已成为有效的 GABAAR 调节剂，可用于产后抑郁症和难治性癫痫等疾病。分子生物学和药理学的进步促进了同工酶特异性调节剂的开发，从而有可能减少脱靶效应并提高治疗效果。此外，将 GABAAR 调节剂与其他治疗药物结合使用，有望提高疗效并减少副作用。本综述重点介绍了这些化合物的设计策略、药效学、临床疗效和安全性，强调了开发新型 GABAAR 调节剂以改善治疗效果的机会。
Clinical applications of small-molecule GABAAR modulators for neurological disorders.
Gamma-aminobutyric acid type A receptor (GABAAR) 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 GABAAR modulators. Benzodiazepines, such as Diazepam, are well-known positive allosteric modulators (PAMs) that enhance GABAAR 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 GABAAR, reducing some of these side effects. Neurosteroids such as allopregnanolone and its synthetic analogs, including Brexanolone, have emerged as potent GABAAR 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 GABAAR 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 GABAAR modulators with improved therapeutic outcomes.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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