Phosphodiesterase 10A (PDE10A) is an intracellular protein that is located almost exclusively within the basal ganglia. It plays an important role in information transfer within this region and could therefore be of great importance in motor control in general and Parkinson’s disease (PD) in particular. Aim of the present project is to test the hypothesis that PDE10 inhibitors may be beneficial for the treatment of PD or for the treatment of L-DOPA induced dyskinesias.
In part 1, we will perform a proof-of-concept study, by investigating the effects of a highly selective PDE10A inhibitor on the turning behaviour in a pre-clinical model. In addition, we will evaluate whether this PDE10A is effective in counteracting the dyskinesias seen after repeated treatment with L-DOPA in the pre-clinical model. If either of these studies shows a positive result, Evotec has a project plan in place to progress the programme through hit to lead and lead and lead optimization (described in the original application).
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, there is virtually no scientific data that supports the therapeutic use of PDE 10 inhibitors in the treatment of PD, in spite of its specific localization in the region of the brain which are affected in these patients. Since selective PDE10A inhibitors have recently been reported and these drugs, in rats, seem to have little side effects so far, the time is ripe to investigate their usefulness as a novel therapy.
If we can show a positive effect in the proof on concept study, we intend to further continue to develop a selective PDE10A inhibitor which can serve as a preclinical development candidate for treatment trials in patients.
PDE10A is highly expressed in medium spiny neurons of the direct and indirect striatal pathways and as such it is suitably located to modulate the output pathways of the striatum that are dysfunctional in Parkinson’s disease. The goal of this project was to evaluate the potential anti-parkinsonian action of the highly selective PDE10A inhibitor, MP-10, and its effects on levodopa-induced dyskinesias in the 6-OHDA pre-clinical model of Parkinson’s disease.
Studies carried out to date indicate that MP-10 was able to reduce levodopa-induced abnormal involuntary movements in 6-OHDA pre-clinical model of Parkinson’s disease. The effect was of similar magnitude to that observed with amantadine, the only drug currently approved for treatment of levodopa-induced dyskinesias. However, the effect was only observed in a narrow dose range and the anti-dyskinetic activity was lost at higher doses. Unlike lovedopa, MP-10 did not possess anti-parkinsonian activity when administered alone and had no effect on locomotor activity induced by levodopa.