TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia.

TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia. CNS Neurosci Ther. 2018 Jan 09;: Authors: Suzuki K, Kimura H Abstract The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D2 receptor antagonism or partial agonism, phosphodiesterase 10A (PDE10A) inhibitors activate indirect pathway MSNs, leading to the expectation of therapeutic potential for the treatment of psychosis. PDE10A inhibitors also activate direct pathway MSNs which may be associated with cognitive functions. These pathways have competing effects on antipsychotic-like activities and extrapyramidal symptoms in rodents. Therefore, careful consideration of activation pattern of these pathways by a PDE10A inhibitor is critical to produce potent efficacy and superior safety profiles. In this review, we outline the pharmacological profile of TAK-063, a novel PDE10A selective inhibitor. Our study revealed that off-rates of PDE10A inhibitors may characterize their pharmacological profiles via regulation of each MSN pathway. TAK-063, with a faster...
Source: CNS Neuroscience and Therapeutics - Category: Neuroscience Authors: Tags: CNS Neurosci Ther Source Type: research