发现中枢神经系统相关疾病的PDE10A抑制剂的进展。 第2部分：专注于精神分裂症

Title:Advances in the Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 2: Focus on Schizophrenia

Volume: 20 Issue: 16

关键词: PDE10A抑制剂，多功能配体，抗精神病活性，认知活性，精神分裂症，临床试验。

摘要:

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.

Cite this article as:

Advances in the Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 2: Focus on Schizophrenia, Current Drug Targets 2019; 20 (16) . https://dx.doi.org/10.2174/1389450120666190801114210