PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMR Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1

exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 Selleckchem Silmitasertib Rabusertib concentration significantly increased phosphorylation

of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’. (C) 2012 Elsevier Ltd. All rights reserved.”
“The purpose was to assess the validity of predicting peak oxygen uptake ((V) over dotO(2)peak) from Ratings of Perceived Exertion volitional

exhaustion. During GXT, oxygen uptake (VO(2)) and RPE were measured Individual linear regressions between (V) over dotO(2) and RPE < 15 were extrapolated to RPE 20 in until order to predict (V) over dotO(2)peak Actual and predicted VO(2)peak were not significantly different (13.9 +/- 3.0 vs 14.2 +/- 3.3 ml kg(-1) min(-1), respectively, p = 26) The Pearson product moment correlation between actual and predicted (V) over dotO(2)peak was high (r = 0 82). The 95% limits of agreement analysis on these values (bias +/- 1 96SD) was -0.3 +/- 3.7 ml kg(-1) min(-1). Results suggested that RPE <= 15 elicited during a sub-maximal GXT provides accurate VO(2)peak prediction. Therefore, it is not necessary to perform GXT to voluntary exhaustion to determine VO(2)peak in obese women.”
“The demonstrated functional interaction of metabotropic glutamate 5 (mGlu(5)) receptors with N-methyl-D-aspartate (NMDA) receptors has prompted speculation that their activation may offer a potential treatment for aspects of schizophrenia.