Phosphodiesterases in the CNS: targets for drug development

Abstract

The therapeutic and commercial success of phosphodiesterase 5 inhibitors such as Viagra, Levitra and Cialis has sparked renewed interest in the phosphodiesterases as drug discovery targets. Virtually all the phosphodiesterases are expressed in the CNS, making this gene family a particularly attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. Significantly, all neurons express multiple phosphodiesterases, which differ in cyclic nucleotide specificity, affinity, regulatory control and subcellular compartmentalization. Therefore, phosphodiesterase inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. In this article, we review the current state of the art in the burgeoning field of phosphodiesterase pharmacology in the CNS.

Key Points

  • 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.

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Figure 1: Hypothetical compartmentalization and coupling of second messenger signalling by phosphodiesterases.
Figure 2: The domain structure of the phosphodiesterases.
Figure 3: Structures of selected examples of phosphodiesterase inhibitors.
Figure 4: Efficiencies gained in moving from a single-target approach to a gene-family process.

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Acknowledgements

We thank C. A. Strick and L. James for providing data on PDE expression in mouse striatum, C.A.S, M. O'Donnell and D. Stephenson for images of PDE immunohistochemistry and J. Harms for cGMP data. We also thank X. Hou and R. Chambers for helpful discussions on targeting PDE inhibitors to the CNS.

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Correspondence to Christopher J. Schmidt.

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Competing interests

The authors are employees of Pfzier Inc, which developed and markets sildenafil.

Glossary

Subcellular compartmentalization

A specific environment or location within a cell structure that is separate and distinct from other components of the cell.

Long-term potentiation

(LTP). The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.

Auditory evoked potentials

An electrical response recorded in different brain regions to a discrete auditory stimulus that represents the ensemble firing of different neuronal populations.

Forced swim test and tail suspension test

Behavioural tests in rodents in which the latency to, and/or duration of, immobility is used as an index of behavioural despair. Antidepressants increase latency to, and decrease duration of, immobility.

Single nucleotide polymorphism

(SNP). A location in a DNA sequence at which different nucleotides are present across a population. Differences in a single nucleotide could change the protein sequence or regulation of gene expression. This might be associated with a difference in susceptibility to a disease, or could have no consequence.

Synaptic plasticity

A change in the functional properties of a synapse as a result of use.

Spontaneous alternation

A behavioural test in which rodents will spontaneously alternate visits to different locations in a maze, reflecting a natural foraging strategy. This requires animals to remember their previous response, and is therefore a measure of memory function.

Conditioned avoidance response

A behavioural test in which animals are trained to avoid a shock by responding to a signal stimulus. All clinically useful antipsychotic agents inhibit this response.

Pharmacophore

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

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