Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Future Med Chem. 2014 Jan;6(1):57-75. doi: 10.4155/fmc.13.158.
The introduction of typical antipsychotics over six decades ago signaled an important milestone in psychiatry. However, second-generation antipsychotics ameliorated the positive symptoms of schizophrenia but displayed limited effectiveness for the negative and cognitive symptoms. In addition, while the newer antipsychotics produced fewer motor side effects, the atypical antipsychotics still induced weight gain and endocrinopathies. In recent years, a third generation of antipsychotics was identified. Aripiprazole was the first approved drug acting as a D2 partial agonist/functionally selective ligand. This review presents the state of the development of novel antipsychotic dopaminergic and non-dopaminergic agents, supported by an overview of the compounds evaluated under advanced preclinical and clinical development (e.g., cariprazine and brexpiprazole). In line with the recent trends in the development of modern atypical antipsychotics, we present our strategic development of long-chain arylpiperazine-derived quinoline- and isoquinoline-sulfonamide displaying a multireceptor binding profile and partial D2 receptor agonism.
六十多年前典型抗精神病药物的问世标志着精神病学的一个重要里程碑。然而，第二代抗精神病药物改善了精神分裂症的阳性症状，但对阴性和认知症状的疗效有限。此外，虽然新型抗精神病药物较少引起运动副作用，但非典型抗精神病药物仍会导致体重增加和内分泌疾病。近年来，第三代抗精神病药物被确定。阿立哌唑是第一个被批准的作为 D2 部分激动剂/功能选择性配体的药物。本综述介绍了新型抗精神病药物多巴胺能和非多巴胺能药物的发展现状，概述了处于先进临床前和临床开发阶段的化合物（例如卡利哌嗪和布瑞哌唑）。根据现代非典型抗精神病药物开发的最新趋势，我们介绍了我们对长链芳基哌嗪衍生的喹啉和异喹啉磺酰胺的战略开发，这些化合物显示出多受体结合谱和部分 D2 受体激动作用。
