The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey

Smith, Sean M.; Uslaner, Jason M.; Cox, Christopher D.; Huszar, Sarah L.; Cannon, Christopher E.; Vardigan, Joshua D.; Eddins, Donnie; Toolan, Dawn; Kandebo, Monika; Yao, Lihang; Raheem, Izzat T.; Schreier, John D.; Breslin, Michael J.; Coleman, Paul J.; Renger, John J.

doi:10.1016/j.neuropharm.2012.06.013

Cited by 79 publications

(61 citation statements)

References 56 publications

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“…In Vitro PDE Activity Assays PDE activity was determined in duplicate at room temperature using an IMAP FP kit (Molecular Devices, Sunnyvale, CA) (20). Human PDE10A2 and rhesus monkey PDE2A3 enzymes were prepared from cytosolic fractions of transiently transfected AD293 cells, as described (20).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

“…Human PDE10A2 and rhesus monkey PDE2A3 enzymes were prepared from cytosolic fractions of transiently transfected AD293 cells, as described (20). All other PDEs (PDE1A, PDE3A, PDE4A1A, PDE5A1, PDE6C, PDE7A, PDE8A1, PDE9A2, and PDE11A4) were glutathione S-transferase-tagged human enzymes expressed in insect cells and were obtained from BPS Bioscience (San Diego, CA).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

“…All other PDEs (PDE1A, PDE3A, PDE4A1A, PDE5A1, PDE6C, PDE7A, PDE8A1, PDE9A2, and PDE11A4) were glutathione S-transferase-tagged human enzymes expressed in insect cells and were obtained from BPS Bioscience (San Diego, CA). The apparent inhibition constant (K i ) for THPP-1 against the 11 PDEs was determined using the apparent K M values for each enzyme, as described by Smith et al (20).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

“…PDE10A-deficient mice show reduced exploratory behavior when placed in a novel environment and have a blunted response to the psychomotor activating effects of N-methyl-D-aspartate receptor (NMDA) receptor antagonists phencyclidine and MK-801 (15,16). Selective PDE10A inhibitors decrease psychomotor activity, reverse deficits in prepulse inhibition, and inhibit conditioned avoidance responding in rodents, models that are predictive of antipsychotic activity in the clinic (17)(18)(19)(20)(21). PDE10A inhibitors are also efficacious in preclinical assays that test cognitive domains impaired in schizophrenia (17,20,22,23) and models of negative symptoms (17).…”

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confidence: 99%

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Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

et al. 2013

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Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

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Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

et al. 2013

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“…Given the high level of expression of PDE10A in MSNs, PDE10A inhibitors are thought to increase cyclic nucleotide levels and activate downstream signal transduction in the striatum, similar to D 2 antagonists in indirect pathway neurons. PDE10A inhibitors have also shown a promising pharmacological profile in rodents as therapeutic drugs for schizophrenia (Grauer et al, 2009;Megens et al, 2014;Schmidt et al, 2008;Smith et al, 2013). However, in a 4-week phase 2a proof-of-concept trial, Pfizer's PDE10A inhibitor MP-10 (PF-02545920) was not superior to placebo in patients with an acute exacerbation of their symptoms of schizophrenia (DeMartinis et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Suzuki

Harada

Suzuki

et al. 2016

Neuropsychopharmacol

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Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D 1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D 2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.

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Pharmacological Manipulation of Cyclic Nucleotide Phosphodiesterase Signaling for The Treatment of Neurological and Psychiatric Disorders In The Brain

Menniti

Plath

Svenstrup

et al. 2014

Cyclic‐Nucleotide Phosphodiesterases in the Central Nervous System

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The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey

Cited by 79 publications

References 56 publications

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Pharmacological Manipulation of Cyclic Nucleotide Phosphodiesterase Signaling for The Treatment of Neurological and Psychiatric Disorders In The Brain

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