Phosphodiesterase 10A Inhibitor Activity in Preclinical Models of the Positive, Cognitive, and Negative Symptoms of Schizophrenia

Abstract

Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quino-line], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.Phosphodiesterase 10A (PDE10A) inhibition has generated much excitement as a potential novel mechanism for the treatment of the positive symptoms of schizophrenia (Menniti et al., 2007;Siuciak, 2008 ABBREVIATIONS: PDE10A, phosphodiesterase 10A; MP-10, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethy]-quinoline; TP-10, 2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline; MK-801, dizocilpine maleate; CREB, cAMP-response element-binding protein; pCREB, phospho-cAMP-response element-binding protein; DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass; pDARPP-32, phosphodopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass; PKA, protein kinase A; cGKII, cGMP-dependent kinase type II; D1, dopamine receptor subtype 1; D2, dopamine receptor subtype 2; GluR1, glutamate receptor subunit 1; pGluR1, phosphoglutamate receptor subunit 1; GluR2/3, glutamate receptor subunit 2/glutamate receptor subunit 3; pGluR2/3, phosphoglutamate receptor subunit 2/phosphoglutamate receptor subunit 3; NMDA, N-methyl-D-aspartate; NR2B, NMDA ...

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

“…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).…”

“…During assessment of expression changes in pathway-specific markers, PDE10A inhibition resulted in activation of both direct and indirect pathways (Grauer et al, 2009;Suzuki et al, 2015). The combined enhancement of both D 1 receptor expressing the direct pathway and D 2 receptor expressing the indirect pathway could contribute to behavioral effects that differ from those of current antipsychotics.…”

“…did not significantly increase PPI in C57BL/6J mice, although it showed significant upregulation of cyclic nucleotide levels and their downstream signaling at 3 mg/kg i.p. (Grauer et al, 2009). …”

Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay

“…Moreover, PDE10A inhibition caused by papaverine effectively improved executive function deficits associated with experimental schizophrenia in rats [10] . Selective PDE10A inhibitors TP-10 and MP-10 have been reported to decrease psychomotor activity, reverse deficits in prepulse inhibition and inhibit conditioned avoidance response (CAR) in rodents, implying potential antipsychotic activities [11,12] . These compounds also improved cognitive performance in domains impaired in schizophrenia and negative symptoms in rodents [11][12][13] .…”

“…Selective PDE10A inhibitors TP-10 and MP-10 have been reported to decrease psychomotor activity, reverse deficits in prepulse inhibition and inhibit conditioned avoidance response (CAR) in rodents, implying potential antipsychotic activities [11,12] . These compounds also improved cognitive performance in domains impaired in schizophrenia and negative symptoms in rodents [11][12][13] . As mentioned above, it is believed that novel PDE10 inhibitors would serve not only as potential drug candidates to treat psychosis, but also as important tools to elucidate the mechanisms of action related to PDE10.…”