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

(E-pub Ahead of Print)

Author(s): Artur Świerczek, Agnieszka Jankowska, Grażyna Chłoń-Rzepa, Maciej Pawłowski, Elżbieta Wyska*.

Journal Name: Current Drug Targets

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Abstract:

Schizophrenia is a debilitating mental disorder with relatively high prevalence (~1%), during which three main groups of symptoms occur: positive manifestations (such as psychotic states), negative symptoms (e.g., a withdrawal from social life), and cognitive impairment.

Schizophrenic patients have an excessive release of dopamine in the striatum and an insufficient amounts of this neurotransmitter in the prefrontal cortex. This imbalance is believed to be partially responsible for the occurrence of the three groups of symptoms. Dopamine D2 receptor blockers are the standard treatment of schizophrenia. However, so-called atypical antipsychotics, which additionally act on serotonin 5-HT receptors, are also in use. Nevertheless, the existent treatment of schizophrenia 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, procognitive, and antidepressant functions. Thus, designing of such compounds may constitute a new direction of research for new potential medications for schizophrenia. Moreover, PDE10A inhibitors are currently investigated in other neuropsychiatric and neurodegenerative disorders, thus, the search for new potent inhibitors of this enzyme is still warranted.

Keywords: PDE10A inhibitors, multifunctional ligands, antipsychotic activity, procognitive activity, schizophrenia, clinical trials

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(E-pub Ahead of Print)
DOI: 10.2174/1389450120666190801114210
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