title: The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 attenuates a scopolamine-induced deficit in a novel rodent attention task.
abstract: Numerous changes occur during aging and Alzheimer's disease (AD) progression, including a decline in cholinergic functioning and cognition, as well as alterations in gene expression and activity in the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway. Donepezil, the current standard of care for Alzheimer's disease, improves cholinergic functioning and has demonstrated effects on multiple domains of cognition, including memory and attention in both preclinical species and patients. We previously found that increasing activation of the NO/cGMP pathway via phosphodiesterase 9 (PDE9) inhibition also improves memory in rodents and suggested that PDE9 might be a promising target for novel treatments for AD. Here we investigated whether PDE9 inhibition also enhances attention using a novel attention task in rats. We validated this task using several pharmacological manipulations and showed that the selective PDE9 inhibitor PF-04447943 produced effects similar to those of donepezil. These data confirm and extend the hypothesis that PDE9 inhibition might serve as a novel treatment for AD and age-related cognitive decline.
authors: In-Vivo Pharmacology, Merck & Co, Inc, West Point, PA 19486, USA. Joshua_Vardigan@merck.com
authors: Joshua D
authors: JD
authors: Vardigan
authors: Antonella
authors: A
authors: Converso
authors: Pete H
authors: PH
authors: Hutson
authors: Jason M
authors: JM
authors: Uslaner
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D004195:Disease Models, Animal; D008297:Male; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000009:adverse effects
chemical_list: C572323:6-(4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; D012601:Scopolamine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C481508:Pde9a protein, rat