Phosphodiesterase 10 inhibitors in clinical development for CNS disorders

摘要: Phosphodiesterase 10 inhibitors (PDE10-I), are conceptually attractive drugs with a potential great therapeutic window as their enriched striatal localization may likely stimulate D1R and reduce D2R downstream effects. However, so far selective PDE10-I efficacy in animal models have not shown benefit clinical trials unexpectedly revealed substantial dyskinesia motor side-effect. Areas covered: This paper reviews the underlying biological rationale of PDE10 target schizophrenia, Parkinson's Huntington's disease based on peer-reviewed published articles, status different development for various CNS indications explores possible reasons trial failures translational disconnect. Expert commentary: Possible explanations include non-optimal dose titration schedule, but more importantly differential non-linear pharmacodynamic interactions individual comedications, species difference neurobiology differences rich pharmacology successful antipsychotics. The authors also present optogenetics, DREADD (Designer Receptor Exclusively Activated by Designer Drug) technology, organoids iPSC (induced Pluripotent Stem Cells) advanced computer modeling simulation new technologies to further elucidate complex nature emergent properties key neuronal circuits that drive human behavior.