Burris Kevin D, Molski Thaddeus F, Xu Cen, Ryan Elaine, Tottori Katsura, Kikuchi Tetsuro, Yocca Frank D, Molinoff Perry B
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
J Pharmacol Exp Ther. 2002 Jul;302(1):381-9. doi: 10.1124/jpet.102.033175.
Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.
阿立哌唑是首个新一代非典型抗精神病药物，其作用机制不同于目前市面上的典型和非典型抗精神病药物。在多巴胺能活动减退和亢进的动物模型中，阿立哌唑分别表现出激动剂和拮抗剂的特性。本研究检测了阿立哌唑与单一人群D2受体的相互作用，以进一步阐明其药理特性。在表达重组D2L受体的中国仓鼠卵巢细胞制备的膜中，阿立哌唑与受体的G蛋白偶联状态和解偶联状态均具有高亲和力结合。阿立哌唑能有效激活D2受体介导的cAMP积累抑制作用。使用烷基化剂N - 乙氧基羰基 - 2 - 乙氧基 - 1,2 - 二氢喹啉（EEDQ）进行部分受体失活，显著降低了阿立哌唑对cAMP积累抑制的最大效应。在不改变多巴胺最大抑制效应的EEDQ浓度下可观察到这种效应。与部分激动剂的预期效应一致，阿立哌唑浓度增加会阻断多巴胺的作用，最大阻断程度等于阿立哌唑单独的激动剂效应。阿立哌唑相对于多巴胺的效力在缺乏多巴胺备用受体的细胞中为25%，在有受体储备的细胞中为90%。这些结果，连同先前证明阿立哌唑在5 - 羟色胺（5 - HT）1A受体具有部分激动剂活性以及在5 - HT2A受体具有拮抗剂活性的研究，支持将阿立哌唑鉴定为多巴胺 - 5 - 羟色胺系统稳定剂。受体活性谱可能是阿立哌唑在动物中独特活性及其在人类中的抗精神病活性的基础。
