The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models

Abstract

Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl) phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4 (1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-D-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.

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 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts . These findings suggest that TAK‐063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.…”

“…Besides antipsychotic‐like effects, differential activation pattern of MSNs may also affect other pharmacological properties of PDE10A inhibitors. Interestingly, different from TAK‐063, MP‐10 did not significantly inhibit ketamine‐induced increase in EEG gamma power and did not produced cognitive improvement in novel object recognition task in rats . Differential activation pattern of MSNs may affect the modulation of cortical activity by PDE10A through the striato‐thalamo‐cortical circuit.…”

“…These findings suggest that the antipsychotic‐like efficacy of TAK‐063 may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways (Figure I). In addition to antipsychotic‐like efficacy, TAK‐063 enhanced cognitive function associated with schizophrenia in rodent models . TAK‐063 may provide an opportunity for further evaluation of PDE10A inhibition as a novel therapeutic strategy for psychosis and cognitive deficits in schizophrenia.…”

“…TAK‐063 is a novel PDE10A inhibitor with a potent inhibitory activity (hPDE10A IC 50 = 0.30 nmol/L; Figure A) and high selectivity (>15 000‐fold) over other PDE families (PDE1–PDE11) in in vitro assays using recombinant human enzymes . Further assessment of in vitro selectivity of TAK‐063 showed that TAK‐063 at 10 μmol/L did not show more than 50% inhibition or stimulation of 91 target molecules, except for PDEs .…”

“…Integrated striatal outputs following inhibition of PDE10A in both MSN pathways may improve cognitive function by modifying cortical activity. Accordingly, several PDE10A inhibitors have demonstrated improved cognitive function in animal models . PDE10A inhibitors may also have potential therapeutic utility in the treatment of cognitive impairment associated with schizophrenia.…”