Phosphodiesterase 9A (PDE9A) is a cGMP-specific phosphodiesterase (PDE) with the highest affinity for cGMP (Km = 170 nM) of any mammalian PDE. Cyclic nucleotides are critical regulators of synaptic plasticity, and they participate in requisite signaling cascades implicated across multiple neurotransmitter systems, thus making PDE9A an excellent candidate to serve as a therapeutic target for modulation of basal levels of cGMP in the brain. Kleiman et al. developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. In vivo effects of PDE9A inhibition included reversal of the disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. These results demonstrate a role for PDE9A-mediated cGMP signaling in the modulation of tasks dependent upon hippocampal cholinergic function and sensory gating. It was proposed that inhibition of PDE9A may provide therapeutic benefit in patient populations suffering from cognitive deficits and exhibiting disrupted sensory processing, such as those with Alzheimer's disease, schizophrenia, and/or Huntington's disease.
See article at J Pharmacol Exp Ther 2012, 341:396–409.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics