Anxioselective Compounds Acting at the GABAA Receptor Benzodiazepine Binding Site
Anxioselective Compounds Acting at the GABAA Receptor Benzodiazepine Binding Site
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DOI：
10.2174/1568007033482841
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发表时间：
2003-01-01
影响因子：
3
通讯作者：
Atack, John R.
中科院分区：
文献类型：
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作者：
Atack, John R.
除强迫症外，苯二氮卓类药物（BZ）仍然是焦虑症的主要一线治疗药物。然而，除了抗焦虑外，BZ还引起急性镇静，这与BZ也用作催眠药的事实有关，并且长期可能具有滥用潜力以及引起身体依赖性，这表现为停药后出现许多不良事件。BZ的分子机制现已明确，因为它们通过结合到含有α 1、α 2、α 3和α 5亚基的GABA（A）受体上的特异性识别位点来增强抑制性神经递质GABA的作用。在该调节位点结合并增强GABA的抑制作用的化合物被归类为激动剂，降低GABA作用的化合物被称为反向激动剂，而结合但对GABA抑制没有影响的化合物被称为拮抗剂。临床上使用的BZ是完全激动剂，并且在谱的相对端之间，即完全激动剂和完全反向激动剂，是具有不同程度功效的一系列化合物，已经尝试开发具有抗焦虑选择性的化合物，因为它们保留了完全激动剂BZ的抗焦虑性质，但具有降低的镇静和依赖性（退出）负债。这类化合物可与所有四种（即含有α 1-、α 2-、α 3-和α 5-的）GABA（A）受体亚型相互作用，并具有部分而非完全激动剂功效。非选择性部分激动剂的实例包括布他西尼、咪达唑尼、FG 8205、abecarnil、NS 2710、帕戈克隆、RWJ-51204和（S）-去甲基佐匹克隆。或者，化合物可能具有相当的结合亲和力，但对各种亚型具有不同的功效，从而优先对被认为与焦虑相关的亚型（含α 2和/或α 3受体）而不是与镇静相关的亚型（含α 1受体）发挥其作用。功效选择性化合物的实例包括L-838417、NGD 91-3和SL 651498。对于每种化合物，将审查临床前和可用的临床数据。新出现的主题包括缺乏某些化合物（例如，abecarnil、ocinaplon、pagoclone）的确定性内在疗效数据，以及难以将临床前物种中非选择性部分激动剂的强效抗焦虑作用和抗焦虑和镇静剂量之间的分离转化为人体中一致的临床获益（例如，bretazenil、abecarnil、pagoclone）。关于疗效选择性化合物，NGD 91-3在人体中不是抗焦虑药，但在缺乏疗效数据的情况下，这些结果难以解释。然而，功效选择性化合物代表了靶向GABA（A）受体的特定亚型的新方法，其最终测试将在临床中进行评估。
With the exception of obsessive compulsive disorder, benzodiazepines (BZs) remain a major first line treatment for anxiety disorders. However, as well as being anxiolytic, BZs also cause sedation acutely, related to the fact that BZs are also used as hypnotics, and chronically may have abuse potential as well as cause physical dependence which manifests itself as the demonstration of a number of adverse events upon discontinuation. The molecular mechanisms of BZs are now well defined in that they enhance the actions of the inhibitory neurotransmitter GABA by binding to a specific recognition site on GABA(A) receptors containing alpha 1, alpha 2, alpha 3 and alpha 5 subunits. Compounds that bind at this modulatory site and enhance the inhibitory actions of GABA are classified as agonists, those that decrease the actions of GABA are termed inverse agonists whereas compounds which bind but have no effect on GABA inhibition are termed antagonists. The clinically used BZs are full agonists and between the opposite ends of the spectrum, i.e. full agonist and full inverse agonist, are a range of compounds with differing degrees of efficacy, such as partial agonists and partial inverse agonists.Attempts have been made to develop compounds which are anxioselective in that they retain the anxiolytic properties of the full agonist BZs but have reduced sedation and dependence (withdrawal) liabilities. Such compounds may interact with all four (i.e. alpha 1-, alpha 2-, alpha 3- and alpha 5-containing) GABA(A) receptor subtypes and have partial rather than full agonist efficacies. Examples of nonselective partial agonists include bretazenil, imidazenil, FG 8205, abecarnil, NS 2710, pagoclone, RWJ-51204 and (S)-desmethylzopiclone. Alternatively, a compound might have comparable binding affinity but different efficacies at the various subtypes, thereby preferentially exerting its effects at subtypes thought to be associated with anxiety (alpha 2- and/or alpha 3-containing receptors) rather than the subtype associated with sedation (alpha 1-containing receptors). Examples of efficacy selective compounds include L-838417, NGD 91-3 and SL651498. For each compound, preclinical and where available clinical data will be reviewed. Emerging themes include the lack of definitive intrinsic efficacy data for certain compounds (e.g. abecarnil, ocinaplon, pagoclone) and the difficulty in translating robust anxiolysis and a separation between anxiolytic and sedative doses of non-selective partial agonists in preclinical species into consistent clinical benefit in man (e.g. bretazenil, abecarnil, pagoclone). With respect to efficacy selective compounds, NGD 91-3 was not anxiolytic in man but in the absence of efficacy data, these results are difficult to interpret. Nevertheless, efficacy selective compounds represent a novel approach to targeting specific subtypes of the GABA(A) receptor, the ultimate test of which will be evaluation in the clinic.