Phosphodiesterases in the CNS: targets for drug development

Cyclic AMP and cyclic GMP are crucial signalling molecules that allow the seamless communication of extracellular signals from diverse membrane-bound transduction systems to tertiary messenger and effector systems within a single cell.Phosphodiesterases (PDEs) are a class of enzymes that regulate cAMP and cGMP concentrations throughout the body.Inhibitors of PDEs (for example, sildenafil, which targets PDE5) have become an important class of drugs, with applications in erectile dysfunction and pulmonary hypertension.The PDE gene superfamily consists of 11 PDE families that are made up of 21 genes that are, in turn, transcribed into more than 50 functionally unique enzymes by alternate splicing.Most PDEs are expressed in the CNS, making this gene superfamily a particularly attractive source of new targets for the treatment of both psychiatric and neurodegenerative disorders.A gene-family drug discovery approach has been used with the PDEs, which enables efficient reagent production, assay development and lead discovery.