Casey Austen B, Canal Clinton E
Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University , Boston, Massachusetts 02115, United States.
ACS Chem Neurosci. 2017 Jun 21;8(6):1135-1146. doi: 10.1021/acschemneuro.7b00087. Epub 2017 Apr 13.
Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D and D and serotonin 5-HT receptors, as well as antagonist activity at serotonin 5-HT receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.
阿立哌唑是首个被开发出对多巴胺 D 自身受体具有激动剂特性的抗精神病药物，这一开创性策略为精神分裂症药物研发开辟了新前景。多巴胺 D 受体是所有现有抗精神病药物的关键靶点，在阿立哌唑之前研发的所有药物均为 D 受体拮抗剂。然而，对这些受体的广泛阻断通常会产生锥体外系（运动）副作用，这困扰着第一代抗精神病药物，如氟哌啶醇。第二代抗精神病药物，如氯氮平，具有独特的多药理学特性和 D 受体结合动力学，其运动副作用风险显著降低，但可能引发大量其他副作用，如严重体重增加和代谢功能障碍。阿立哌唑的多药理学特性表现为其对多巴胺 D 和 D 以及 5-羟色胺 5-HT 受体具有独特的激动剂活性，同时对 5-羟色胺 5-HT 受体具有拮抗剂活性，这使得它能够成功减轻精神分裂症的阳性、阴性和认知症状，同时降低体重增加和运动副作用的风险。然而，新的观察结果将阿立哌唑与一小部分患者的强迫行为联系起来，这是抗精神病药物中一种不寻常的副作用。在这篇综述中，我们讨论了阿立哌唑的化学合成、药理学、药物基因组学、药物代谢和不良事件，并阐述了目前对阿立哌唑神经治疗机制的理解，以及阿立哌唑在神经科学领域的历史和重要性。
