Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology
Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology
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DOI：
10.1038/sj.npp.1300203
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发表时间：
2003-08-01
影响因子：
7.6
通讯作者：
Mailman, R
中科院分区：
文献类型：
--
作者：
Shapiro, DA;Renock, S;Mailman, R
非典型抗精神病药物已经彻底改变了精神分裂症和相关疾病的治疗。目前临床上批准的非典型抗精神病药物的特征在于对D-2-多巴胺受体具有相对低的亲和力和对5-HT 2A血清素受体（5-HT，5-羟色胺（血清素））具有相对高的亲和力。阿立哌唑（OPC-14597）是一种新型的非典型抗精神病药物，据报道是一种高亲和力的D-2-多巴胺受体部分激动剂。我们现在提供阿立哌唑在大量克隆的G蛋白偶联受体、转运蛋白和离子通道中的全面药理学特征。这些数据揭示了阿立哌唑具有亲和力的许多有趣且潜在重要的分子靶标。阿立哌唑对h5-HT 2B-、hD（2L）-和hD（3）-多巴胺受体具有最高亲和力，但对其他几种5-HT受体（5-HT 1A、5-HT 2A、5-HT 7）以及α（1A）-肾上腺素能和hH（1）-组胺受体也具有显著亲和力（5-30 nM）。阿立哌唑对其他G蛋白偶联受体的亲和力较低（30-200 nM），包括5-HT 1D、5-HT 2C、α（1B）-、α（2A）-、α（2B）-、α（2C）-、β（1）-和β（2）-肾上腺素能受体以及H-3-组胺受体。在功能上，阿立哌唑是5-HT 2B受体的反向激动剂，并对5-HT 2A、5-HT 2C、D-3和D-4受体显示部分激动剂作用。有趣的是，我们还发现阿立哌唑对克隆的人D-2-多巴胺受体的功能作用是细胞类型选择性的，并且根据所检查的细胞类型和功能，对克隆的D-2-多巴胺受体的一系列作用（例如激动、部分激动、拮抗）是可能的。对D-2-多巴胺受体的这种功能作用的混合与Lawler等人（1999）提出的假设一致，即阿立哌唑具有“功能选择性”作用。综上所述，我们的研究结果支持这样的假设，即阿立哌唑在人体中的独特作用可能是D-2（可能还有D-3）-多巴胺受体的“功能选择性”激活，以及与选定的其他生物胺受体（特别是5-HT受体亚型（5-HT 1A，5-HT 2A））的重要相互作用的组合。
Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D-2-dopamine receptors and relatively high affinities for 5-HT2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D-2-dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT2B-, hD(2L)-, and hD(3)-dopamine receptors, but also has significant affinity (5-30 nM) for several other 5-HT receptors (5-HT1A, 5-HT2A, 5-HT7), as well as alpha(1A)-adrenergic and hH(1)-histamine receptors. Aripiprazole has less affinity (30-200 nM) for other G protein-coupled receptors, including the 5-HT1D, 5-HT2C, alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(2)-adrenergic, and H-3-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT2B receptors and displays partial agonist actions at 5-HT2A, 5-HT2C, D-3, and D-4 receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D-2-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D-2-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D-2-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has 'functionally selective' actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of 'functionally selective' activation of D-2 (and possibly D-3)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors-particularly 5-HT receptor subtypes (5-HT1A, 5-HT2A).