Radebeul, Germany
Radebeul, Germany
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Reneerkens O.A.H.,Maastricht University | Rutten K.,Maastricht University | Rutten K.,Grunenthal GmbH | Bollen E.,Maastricht University | And 4 more authors.
Behavioural Brain Research | Year: 2013

The objective of this study was to assess the effects of phosphodiesterase type 2 (PDE2) and type 10 (PDE10) inhibition on memory function in the object recognition task using the scopolamine- and MK-801-induced memory deficit model. The effects of the PDE2 inhibitor BAY 60-7550 and the PDE10 inhibitor PQ-10 on object recognition performance were investigated in the scopolamine (0.1. mg/kg, i.p.) or MK-801 (0.125. mg/kg, i.p.) model. BAY 60-7550 was tested at a dose of 0.3-3. mg/kg (p.o.) in both models; PQ-10 was tested at doses of 0.1-1. mg/kg (p.o.) in the scopolamine model and 0.3-3. mg/kg in the MK-801 model. All compounds were injected 30. min before the learning trial. Both BAY 60-7550 (1. mg/kg) and PQ-10 (0.3. mg/kg) attenuated the scopolamine-induced memory deficit. The MK-801-induced memory deficit was reversed after treatment with each PDE inhibitor at a dose of 1. mg/kg or higher. PQ10 was highly brain penetrant, whereas 60-7550 levels in the brain were very low after oral treatment. We concluded that since BAY 60-7550 and PQ10 reversed both scopolamine- and MK-801-induced memory deficits, this supports the notion that dual substrate PDE inhibitors might be suitable candidates for cognition enhancement. © 2012 Elsevier B.V.

Heine C.,University of Leipzig | Sygnecka K.,University of Leipzig | Scherf N.,The Interdisciplinary Center | Scherf N.,TU Dresden | And 4 more authors.
NeuroSignals | Year: 2013

The development of appropriate models assessing the potential of substances for regeneration of neuronal circuits is of great importance. Here, we present procedures to analyze effects of substances on fiber outgrowth based on organotypic slice co-cultures of the nigrostriatal dopaminergic system in combination with biocytin tracing and tyrosine hydroxylase labeling and subsequent automated image quantification. Selected phosphodiesterase inhibitors (PDE-Is) were studied to identify their potential growth-promoting capacities. Immunohistochemical methods were used to visualize developing fibers in the border region between ventral tegmental area/substantia nigra co-cultivated with the striatum as well as the cellular expression of PDE2A and PDE10. The quantification shows a significant increase of fiber density in the border region induced by PDE2-Is (BAY60-7550; ND7001), comparable with the potential of the nerve growth factor and in contrast to PDE10-I (MP-10). Analysis of tyrosine hydroxylase-positive fibers indicated a significant increase after treatment with BAY60-7550 and nerve growth factor in relation to dimethyl sulfoxide. Additionally, a dose-dependent increase of intracellular cGMP levels in response to the applied PDE2-Is in PDE2-transfected HEK293 cells was found. In summary, our findings show that PDE2-Is are able to significantly promote axonal outgrowth in organotypic slice co-cultures, which are a suitable model to assess growth-related effects in neuro(re)generation. Copyright © 2012 S. Karger AG, Basel.

Malamas M.S.,Pfizer | Stange H.,Biocrea | Schindler R.,Biocrea | Lankau H.-J.,Biocrea | And 23 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg). © 2012 Published by Elsevier Ltd.

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