MEDI 264 |
| PDE10A is a dual substrate, cyclic nucleotide phosphodiesterase identified by homology screening and molecular cloning in 1999. Based upon reports of high levels of PDE10A expression in the brain, we have characterized the biological function of PDE10A to evaluate its potential as a CNS drug target. Localization studies across species demonstrate that striatal PDE10A is expressed exclusively in medium spiny neurons of both striatal output pathways. Biochemical and behavioral evaluation of both KO mice and putative inhibitors lead to the hypothesis that PDE10A normally functions to dampen striatal output. Based upon the view that many of the symptoms of schizophrenia are the result of reduced striatal activity, our observations suggest that PDE10A inhibitors would be useful as antipsychotic agents. Consistent with an overall enhancement of striatal function, PDE10A inhibitors potently increase biochemical markers of striatal activity and demonstrate efficacy in preclinical models of antipsychotic activity. Both the biochemical and behavioral effects of PDE10A inhibitors are selectively absent in PDE10A KO mice confirming the mechanism of these activities. As predicted by the presence of PDE10A in both the D2 and D1 receptor expressing pathways, and in contrast to the effects of D2 antagonists, PDE10A inhibitors enhance gene transcription in both striatal output pathways. The opposing effects of these two pathways on motoric function suggest that PDE10A inhibitor may have low EPS liability; an expectation supported in experiments evaluating the cataleptic activity of selective inhibitors. In conclusion, the potent activation of the striatal output indicates that PDE10A inhibitors may be very effective in the treatment of the same symptoms of schizophrenia affected by currently marketed agents. In addition, the unique ability of PDE10A inhibitors to activate both striatal output pathways offers the possibility that these agents will have an improved clinical profile both in terms of safety and efficacy. |
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Phosphodiesterase Inhibitors
1:30 PM-5:00 PM, Wednesday, August 22, 2007 BCEC -- 213, Oral
Division of Medicinal Chemistry |