Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL, USA.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Curr Top Behav Neurosci. 2022;52:81-118. doi: 10.1007/7854_2021_232.
The GABA receptors are metabotropic G protein-coupled receptors (GPCRs) that mediate the actions of the primary inhibitory neurotransmitter, γ-aminobutyric acid (GABA). In the CNS, GABA plays an important role in behavior, learning and memory, cognition, and stress. GABA is also located throughout the gastrointestinal (GI) tract and is involved in the autonomic control of the intestine and esophageal reflex. Consequently, dysregulated GABA receptor signaling is associated with neurological, mental health, and gastrointestinal disorders; hence, these receptors have been identified as key therapeutic targets and are the focus of multiple drug discovery efforts for indications such as muscle spasticity disorders, schizophrenia, pain, addiction, and gastroesophageal reflex disease (GERD). Numerous agonists, antagonists, and allosteric modulators of the GABA receptor have been described; however, Lioresal (Baclofen; β-(4-chlorophenyl)-γ-aminobutyric acid) is the only FDA-approved drug that selectively targets GABA receptors in clinical use; undesirable side effects, such as sedation, muscle weakness, fatigue, cognitive deficits, seizures, tolerance and potential for abuse, limit their therapeutic use. Here, we review GABA receptor chemistry and pharmacology, presenting orthosteric agonists, antagonists, and positive and negative allosteric modulators, and highlight the therapeutic potential of targeting GABA receptor modulation for the treatment of various CNS and peripheral disorders.
GABA 受体是代谢型 G 蛋白偶联受体（GPCRs），可介导主要抑制性神经递质 γ-氨基丁酸（GABA）的作用。在中枢神经系统中，GABA 在行为、学习和记忆、认知以及应激中发挥重要作用。GABA 还分布于整个胃肠道（GI），参与肠道和食管反射的自主控制。因此，GABA 受体信号转导失调与神经、精神健康和胃肠道疾病有关；因此，这些受体已被确定为关键的治疗靶点，并成为多种药物发现努力的重点，用于治疗肌肉痉挛障碍、精神分裂症、疼痛、成瘾和胃食管反流病（GERD）等适应症。已经描述了 GABA 受体的许多激动剂、拮抗剂和变构调节剂；然而，利扎曲坦（Baclofen；β-（4-氯苯基）-γ-氨基丁酸）是唯一一种在临床使用中选择性靶向 GABA 受体的 FDA 批准药物；镇静、肌肉无力、疲劳、认知缺陷、癫痫发作、耐受性和滥用潜力等不良副作用限制了其治疗用途。在这里，我们综述了 GABA 受体的化学和药理学，介绍了变构激动剂、拮抗剂以及正、负变构调节剂，并强调了靶向 GABA 受体调节治疗各种中枢神经系统和外周疾病的治疗潜力。
