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.
