PDE1

2022-08-08: reference:

PDE1 #

AKA Ca-Calmodulin-dependent PDE.

• Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases
• Phosphodiesterase type 1 inhibition alters medial prefrontal cortical activity during goal-driven behaviour and partially reverses neurophysiological deficits in the rat phencyclidine model of schizophrenia
  • PDE1B inhibition may improve memory. Potentiates D1.
• Identification of dual inhibitor of phosphodiesterase 1B/10A using structure-based drug design approach
• PDE1 inhibition decreases D1R agonist-induced cAMP levels and GluA1 surface insertion by activating PDE2: Cross-regulation of Phosphodiesterase 1 and Phosphodiesterase 2 Activities Controls Dopamine-mediated Striatal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Trafficking
• PDE1 inhibition can cause a paradoxical upregulation of PDE2, which impairs cognition.

ITI-214 #

• ITI-214 is an inhibitor: PDE1A, (milder) PDE1B, PDE1C. Activates PDE2A which is antinootropic.
• Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats
  • ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1–10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone.
• Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase-1 improves cognitive performance
  • PDE1 inhibition improves working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels
• Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus
  • knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall.