Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia.
Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920.
The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.
This study presents the pharmacological profile of a novel PDE10A inhibitor, 2-[(E)-2-(7-fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine hydrochloride (T-251) in rodent models of schizophrenia.
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.
The phosphodiesterase 10A (PDE10A) enzyme plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders involving striatal pathology, such as Huntingtońs disease (HD) and schizophrenia.
The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.
TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia.
Therefore, PDE10A inhibitors could be novel therapeutics for schizophrenia, which differ from the currently available antipsychotics that directly block the dopamine D<sub>2</sub> receptor.
Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BP<sub>ND</sub>) of the new validated PDE10A ligand [<sup>11</sup>C]Lu AE92686 between patients with schizophrenia and healthy controls.
Dysregulation of cAMP signaling has been proposed as a cause of bipolar disorder and PDE10A inhibitors have been investigated as potential therapeutics for schizophrenia.
Basal ganglia dysfunction is associated with neuropsychiatric disorders and until recently the development of PDE10A inhibitors has been focused on schizophrenia.
Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia.
Preclinical evidence in a range of animal models suggests that a PDE10A inhibitor could provide efficacy on positive, cognitive and negative symptoms of schizophrenia and PDE10A inhibitors are currently being evaluated in clinical trials for the treatment of schizophrenia.
In the meantime, several novel pharmacological strategies, including activation of mGluRs, elevation of synaptic glycine and inhibition of phosphodiesterase 10A, have recently shown promise for the treatment of schizophrenia in clinical trials.