PDE10A inhibitors: novel therapeutic drugs for schizophrenia

Curr Pharm Des. 2011;17(2):137-50. doi: 10.2174/138161211795049624.

Abstract

Disturbances of the basal ganglia processes is heavily involved in schizophrenia. Phosphodiesterase 10A (PDE10A) is a basal ganglia specific hydrolase, which plays an essential role in regulating cAMP/PKA and cGMP/PKG signalling cascades by controlling the magnitude, duration and cellular location of cAMP/cGMP elevation. Biochemical and behavioral data indicate that PDE10A inhibition activates cAMP/PKA signalling in the basal ganglia, leading to the potentiation of dopamine D₁ receptor signalling, and concomitant inhibition of dopamine D₂ receptor signalling. Preclinical evidence in a range of animal models suggests that a PDE10A inhibitor could provide efficacy on positive, cognitive and negative symptoms of schizophrenia and PDE10A inhibitors are currently being evaluated in clinical trials for the treatment of schizophrenia.

Publication types

  • Review

MeSH terms

  • Animals
  • Basal Ganglia / drug effects*
  • Basal Ganglia / metabolism
  • Clinical Trials as Topic
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*
  • Rats
  • Receptors, Dopamine D1 / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Signal Transduction / drug effects*

Substances

  • Phosphodiesterase Inhibitors
  • Receptors, Dopamine D1
  • Cyclic AMP-Dependent Protein Kinases
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases