Świerczek Artur, Jankowska Agnieszka, Chłoń-Rzepa Grażyna, Pawłowski Maciej, Wyska Elżbieta
Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
Curr Drug Targets. 2019;20(16):1652-1669. doi: 10.2174/1389450120666190801114210.
Schizophrenia is a debilitating mental disorder with relatively high prevalence (~1%), during which positive manifestations (such as psychotic states) and negative symptoms (e.g., a withdrawal from social life) occur. Moreover, some researchers consider cognitive impairment as a distinct domain of schizophrenia symptoms. The imbalance in dopamine activity, namely an excessive release of this neurotransmitter in the striatum and insufficient amounts in the prefrontal cortex is believed to be partially responsible for the occurrence of these groups of manifestations. Second-generation antipsychotics are currently the standard treatment of schizophrenia. Nevertheless, the existent treatment is sometimes ineffective and burdened with severe adverse effects, such as extrapyramidal symptoms. Thus, there is an urgent need to search for alternative treatment options of this disease. This review summarizes the results of recent preclinical and clinical studies on phosphodiesterase 10A (PDE10A), which is highly expressed in the mammalian striatum, as a potential drug target for the treatment of schizophrenia. Based on the literature data, not only selective PDE10A inhibitors but also dual PDE2A/10A, and PDE4B/10A inhibitors, as well as multifunctional ligands with a PDE10A inhibitory potency are compounds that may combine antipsychotic, precognitive, and antidepressant functions. Thus, designing such compounds may constitute a new direction of research for new potential medications for schizophrenia. Despite failures of previous clinical trials of selective PDE10A inhibitors for the treatment of schizophrenia, new compounds with this mechanism of action are currently investigated clinically, thus, the search for new inhibitors of PDE10A, both selective and multitarget, is still warranted.
精神分裂症是一种致残性精神障碍，患病率相对较高（约1%），在此期间会出现阳性症状（如精神病状态）和阴性症状（如退出社交生活）。此外，一些研究人员将认知障碍视为精神分裂症症状的一个独特领域。多巴胺活性失衡，即这种神经递质在纹状体中过度释放而在前额叶皮质中含量不足，被认为部分导致了这些症状群的出现。第二代抗精神病药物目前是精神分裂症的标准治疗方法。然而，现有的治疗方法有时无效且伴有严重的不良反应，如锥体外系症状。因此，迫切需要寻找这种疾病的替代治疗方案。本综述总结了最近关于磷酸二酯酶10A（PDE10A）的临床前和临床研究结果，PDE10A在哺乳动物纹状体中高度表达，是治疗精神分裂症的潜在药物靶点。根据文献数据，不仅选择性PDE10A抑制剂，而且双PDE2A/10A和PDE4B/10A抑制剂，以及具有PDE10A抑制活性的多功能配体，都是可能兼具抗精神病、认知前和抗抑郁功能的化合物。因此，设计这类化合物可能构成精神分裂症新潜在药物研究的一个新方向。尽管先前选择性PDE10A抑制剂治疗精神分裂症的临床试验失败了，但目前具有这种作用机制的新化合物正在进行临床研究，因此，寻找新的选择性和多靶点PDE10A抑制剂仍然是必要的。
