Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27516, USA.
Neuropsychopharmacology. 2011 Feb;36(3):638-51. doi: 10.1038/npp.2010.195. Epub 2010 Nov 3.
Clozapine, by virtue of its absence of extrapyramidal side effects and greater efficacy, revolutionized the treatment of schizophrenia, although the mechanisms underlying this exceptional activity remain controversial. Combining an unbiased cheminformatics and physical screening approach, we evaluated clozapine's activity at >2350 distinct molecular targets. Clozapine, and the closely related atypical antipsychotic drug olanzapine, interacted potently with a unique spectrum of molecular targets. This distinct pattern, which was not shared with the typical antipsychotic drug haloperidol, suggested that the serotonergic neuronal system was a key determinant of clozapine's actions. To test this hypothesis, we used pet1(-/-) mice, which are deficient in serotonergic presynaptic markers. We discovered that the antipsychotic-like properties of the atypical antipsychotic drugs clozapine and olanzapine were abolished in a pharmacological model that mimics NMDA-receptor hypofunction in pet1(-/-) mice, whereas haloperidol's efficacy was unaffected. These results show that clozapine's ability to normalize NMDA-receptor hypofunction, which is characteristic of schizophrenia, depends on an intact presynaptic serotonergic neuronal system.
氯氮平由于其没有锥体外系副作用和更高的疗效，彻底改变了精神分裂症的治疗方法，尽管其背后的机制仍存在争议。我们采用一种无偏见的化学信息学和物理筛选方法，评估了氯氮平在 2350 多个不同分子靶点上的活性。氯氮平和密切相关的非典型抗精神病药物奥氮平，与独特的一系列分子靶点强力相互作用。这种独特的模式与典型抗精神病药物氟哌啶醇不同，表明 5-羟色胺能神经元系统是氯氮平作用的关键决定因素。为了验证这一假设，我们使用了缺乏 5-羟色胺能突触前标志物的 pet1(-/-) 小鼠。我们发现，在模拟 NMDA 受体功能低下的 pet1(-/-) 小鼠药理学模型中，非典型抗精神病药物氯氮平和奥氮平的抗精神病样特性被消除，而氟哌啶醇的疗效不受影响。这些结果表明，氯氮平使 NMDA 受体功能低下正常化的能力，这是精神分裂症的特征，取决于完整的 5-羟色胺能神经元系统。
