Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

Jones, Philip; Hewitt, Michael C.; Campbell, John E.; Quinton, Maria S.; Engel, Sharon; Lew, Robert; Campbell, Una C.; Burdi, Douglas F.

doi:10.1016/j.pbb.2015.04.017

Cited by 12 publications

(6 citation statements)

References 33 publications

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“…In agreement with previous studies with various PDE10A inhibitors (Grauer et al, 2009;Smith et al, 2013;Jones et al, 2015), TAK-063 at 0.1 and 0.3 mg/kg p.o. enhanced retention of recognition memory in rats.…”

Section: Discussionsupporting

confidence: 93%

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

Shiraishi

Suzuki

Harada

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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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.

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Section: Discussionsupporting

confidence: 93%

“…Integrated striatal outputs following inhibition of PDE10A may improve cognitive functions by modifying cortical activity. Accordingly, several PDE10A inhibitors have been shown to improve cognitive functions in animal models (Rodefer et al, 2005;Grauer et al, 2009;Smith et al, 2013;Jones et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Shiraishi

Suzuki

Harada

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…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.…”

Section: Pde10a As a Promising Target For Novel Antipsychoticsmentioning

confidence: 99%

“…Accordingly, several PDE10A inhibitors have demonstrated improved cognitive function in animal models. [39][40][41][42] PDE10A inhibitors may also have potential therapeutic utility in the treatment of cognitive impairment associated with schizophrenia.…”

Section: Pde10a As a Promising Target For Novel Antipsychoticsmentioning

confidence: 99%

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

Suzuki

Kimura

2018

CNS Neurosci Ther

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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 D 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 off-rate property, could provide a unique opportunity as a novel therapeutic approach to treatment of psychosis and cognitive deficits in schizophrenia. TAK-063 also has a therapeutic potential in other basal ganglia disorders.

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“…In conditioned avoidance responding (CAR), an animal model predictive of drug antipsychotic activity, PDE10A inhibitors exhibited a dose-dependent inhibition. (Jones et al, 2015 ; Suzuki et al, 2015 ). Great efforts have been devoted in the development of PDE10 inhibitors in the last decade.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities

Chen

Deng

et al. 2018

Front. Chem.

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Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

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Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

Cited by 12 publications

References 33 publications

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

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

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

Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities

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