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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selective anxiolysis produced by ocinaplon, a GABA_A receptor modulator
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Selective anxiolysis produced by ocinaplon, a GABA_A receptor modulator

机译：由GABA_A受体调节剂ocinaplon产生的选择性抗焦虑作用

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Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselec-tive agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses > 25-fold higher than the minimum effective dose (3.1 mg/kg) in the Vogel "conflict" test. This anticonflict effect is blocked by flumazenil (Ro 15-1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABAA receptors. Nonetheless, in eight recombinant GABAA receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180-240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders.
机译：苯二氮卓类药物尽管表现出突出的，常常是有限的副作用，包括镇静，肌肉松弛和共济失调，但仍广泛用于治疗焦虑症。产生与苯二氮卓类药物相当的抗焦虑作用但在治疗剂量下没有这些局限性副作用的化合物（抗焦虑药），将代表治疗广泛性焦虑症和其他焦虑症的重要进展。在这里，我们报道吡唑并[1,5-a]-嘧啶，ocinaplon在临床前程序和广泛性焦虑症（最常见的焦虑症）患者中均表现出焦虑选择性。在大鼠中，ocinaplon仅比Vogel“冲突”测试中的最小有效剂量（3.1 mg / kg）高25倍以上，才能产生明显的肌肉松弛，共济失调和镇静作用。氟马西尼（Ro 15-1788）阻止了这种抗冲突作用，这表明像苯二氮卓类药物一样，ocinaplon通过变构调节GABAA受体产生抗焦虑作用。尽管如此，在非洲爪蟾卵母细胞中表达的八种重组GABAA受体同工型中，八倍体对增强GABA反应的效力和功效不仅在绝对意义上随亚基组成而变化，而且相对于典型的苯二氮卓地西epa也有所不同。在一项双盲，安慰剂对照的临床试验中，使用2周的ocinaplon方案（每日总剂量为180-240 mg）可使汉密尔顿焦虑量表的评分范围显着降低。在这项研究中，用ocinaplon治疗的患者中苯二氮卓类副作用（例如镇静，头晕）的发生率与安慰剂没有差异。这些发现表明，ocinaplon代表了治疗和理解焦虑症的独特方法。

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