GABAA agonists and partial agonists:: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic
GABAA agonists and partial agonists:: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic
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DOI：
10.1016/j.bcp.2004.06.040
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发表时间：
2004-10-15
影响因子：
5.8
通讯作者：
Ebert, B
中科院分区：
文献类型：
--
作者：
Krogsgaard-Larsen, P;Frolund, B;Ebert, B
GABA(A) 受体系统与许多中枢神经系统 (CNS) 疾病有关，因此 GABA(A) 受体配体作为潜在的治疗剂受到关注。目前已知只有少数不同类别的结构可作为异源五聚体 GABA(A) 受体复合物上 GABA 识别位点的配体，这反映了 GABA(A) 受体识别和激活的非常严格的结构要求。许多在 GABA(A) 受体位点表现出激动剂活性的化合物在结构上均源自我们在项目初始阶段开发的 GABA(A) 激动剂蝇蕈醇、THIP（加波沙朵）或异口疫苗。使用重组 GABA(A) 受体，包括 THIP 在内的许多化合物都显示出功能选择性，显示出亚基依赖性效力和最大反应。 THIP 的药理学和临床活性可能反映了其对对苯二氮卓类药物不敏感且含有 α(4)β(3)δ 亚基的突触外 GABA(A) 受体的有效作用。正在进行的关于部分 GABA(A) 激动剂 THIP 对人类睡眠模式影响的临床研究结果表明，直接作用的激动剂的功能后果与给予 GABA(A) 受体调节剂（如苯二氮卓类药物）后观察到的功能后果明显不同。鉴于人们对部分 GABA(A) 受体激动剂作为潜在治疗药物的兴趣，已经对 4-PIOL（一种源自 THIP 的低效部分 GABA(A) 激动剂）的许多类似物进行了结构活性研究。在这方面，已经开发了一系列 GABA(A) 配体，显示出从低效部分 GABA(A) 激动剂活性到选择性拮抗剂作用的药理学特征。 (C) 2004 Elsevier Inc. 保留所有权利。
The GABA(A) receptor system is implicated in a number of central nervous system (CNS) disorders, making GABA(A) receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABA(A) receptor complex, reflecting the very strict structural requirements for GABA(A) receptor recognition and activation. A large number of the compounds showing agonist activity at the GABA(A) receptor site are structurally derived from the GABA(A) agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA(A) receptors, functional selectivity has been shown for a number of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA(A) receptors insensitive to benzodiazepines and containing alpha(4)beta(3)delta subunits. The results of ongoing clinical studies on the effect of the partial GABA(A) agonist THIP on human sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA(A) receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA(A) receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA(A) agonist derived from THIP, have been performed. In this connection, a series of GABA(A) ligands has been developed showing pharmacological profiles ranging from low-efficacy partial GABA(A) agonist activity to selective antagonist effect. (C) 2004 Elsevier Inc. All rights reserved.