title: PDE10A inhibitors: novel therapeutic drugs for schizophrenia.
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.
authors.affiliation: H. Lundbeck A/S, Department of Medicinal Chemistry & DMPK, Ottiliavej 9, DK-2500 Valby, Denmark. jke@lundbeck.com
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
authors.forename: Jacob
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D002986:Clinical Trials as Topic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D010726:Phosphodiesterase Inhibitors; D017447:Receptors, Dopamine D1; D017868:Cyclic AMP-Dependent Protein Kinases; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases