Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Phosphodiesterases in the CNS: targets for drug development

Nature Reviews Drug Discovery volume 5, pages 660–670 (2006)Cite this article

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.

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Sutherland, E. W. Studies on the mechanism of hormone action. Science 177, 401–408 (1972).

    Article  CAS  PubMed  Google Scholar 

  2. Houslay, M. D. Compartmentalization of cyclic AMP phosphodiesterases, signaling 'crosstalk', desensitization and the phosphorylation of Gi-2 add cell specific personalization to the control of the levels of the second messenger cyclic AMP. Advan. Enzyme Regul. 35, 303–338 (1995).

    Article  CAS  Google Scholar 

  3. Houslay, M. D. & Adams, D. R. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem. J. 370, 1–18 (2003). Comprehensive review of the physiology of PDE4. The principles regarding the structure and compartmentalization of PDE4 apply widely to the other phosphodiesterases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baillie, G. S. & Houslay, M. D. Arrestin times for compartmentalised cAMP signaling and phosphodiesterase-4 enzymes. Curr. Opin. Cell Biol. 17, 129–134 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Finn, J. T., Grunwald, M. E. & Yau, K. W. Cyclic nucleotide-gated ion channels: an extended family with diverse functions. Annu. Rev. Physiol. 58, 395–426 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Beltman, J., Sonnenburg, W. K. & Beavo, J. A. The role of protein phosphorylation in the regulation of cyclic nucleotide phosphodiesterases. Mol. Cell. Biochem. 127, 239–253 (1993).

    Article  PubMed  Google Scholar 

  7. Kawaski, H. et al. A family of cAMP-binding proteins that directly activate Rap1. Science 282, 2275–2279 (1998).

    Article  Google Scholar 

  8. Bos, J. L. EPAC: a new cAMP target and new avenues in cAMP research. Nature Rev. Mol. Cell Biol. 4, 733–738 (2003).

    Article  CAS  Google Scholar 

  9. Colledge, M. & Scott, J. D. AKAPs: from structure to function. Trends Cell Biol. 9, 216–221 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Lugnier, C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol. Ther. 109, 366–398 (2006). A recent comprehensive review of the PDE superfamily.

    Article  CAS  PubMed  Google Scholar 

  11. Beavo, J. A., Conti, M. & Hasslip, R. J. Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 46, 399–405 (1994).

    CAS  PubMed  Google Scholar 

  12. Houslay, M. D. & Milligan, G. Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem. Sci. 22, 217–224 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Sasaki, T., Kotera, J. & Oomori, K. Novel alternative splice variants of rat phosphodiesterase 7B showing unique tissue-specific expression and phosphorylation. Biochem. J. 361, 211–220 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xie, Z. et al. Cellular and subcellular localization of PDE10A, a striatal-specific phosphodiesterase. Neuroscience 139, 597–607 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Noyama, K. & Maekawa, S. Localization of cyclic nucleotide phosphodiesterase 2 in the brain-derived Triton-insoluble low-density fraction (raft). Neurosci. Res. 45, 141–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Cherry, J. A. & Davis, R. L. Cyclic AMP phospho-diesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J. Comp. Neurol. 407, 287–301 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Houslay, M. D., Schafer, P. & Zhang, K. Y. Phosphodiesterase-4 as a therapeutic target. Drug Discov. Today 10, 1503–1519 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Dudai, Y., Jan, Y. N., Byers, D., Quinn, W. G. & Benzer, S. dunce, a mutant of Drosophila deficient in learning. Proc. Natl Acad. Sci. USA 73, 1684–1688 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rose, G. M., Hopper, A., De Vivo, M. & Tehim, A. Phosphodiesterase inhibitors for cognitive enhancement. Curr. Pharm. Des. 11, 3329–3334 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Barad, M., Bourtchouladze, R., Winder, D. G., Golan, D. G. & Kandel, E. R. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc. Natl Acad. Sci. USA 95, 15020–15025 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Monti, B., Berteotti, C. & Contestabile, A. Subchronic Rolipram delivery activates hippocampal CREB and Arc, enhances retention and slows down extinction of conditioned fear. Neuropsychopharmacology 31, 278–286 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. O'Donnell, J. M. & Zhang, H. T. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol. Sci. 25, 158–163 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Zeller, E. Results of a phase II study of the antidepressant effect of rolipram. Pharmacopsychiatry 17, 188–190 (1984).

    Article  CAS  PubMed  Google Scholar 

  24. Monnet, F. P. Transcription and neurotrophic factors in affective disorders: new trends in understanding the action of antidepressant drugs. Curr. Psychiatry Rev. 1, 313–317 (2005).

    Article  CAS  Google Scholar 

  25. Nakagawa, S. et al. Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J. Neurosci. 22, 3673–3682 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nibuya, M., Nestler, E. J. & Duman, R. S. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J. Neurosci. 16, 2365–2372 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Maxwell, C. R., Kanes, S. J., Abel, T. & Siegel, S. J. Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications. Neuroscience 129, 101–107 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Millar, J. K. et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310, 1128–1129 (2005).

    Article  CAS  Google Scholar 

  29. Yamashita, N., Hayashi, A., Baba, J. & Sawa, A. Rolipram, a phosphodiesterase-4-selective inhibitor, promotes the survival of cultured rat dopaminergic neurons. Jpn. J. Pharmacol. 75, 155–159 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Akaike, N., Furukawa, K. & Kogure, K. Rolipram enhances the development of voltage-dependent Ca2+ current and serotonin-induced current in rat pheochromocytoma cells. Brain Res. 620, 58–63 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Pearse, D. D. et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nature Med. 10, 610–616 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Gao, Y., Nikulina, E., Mellado, W. & Filbin, M. T. Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. J. Neurosci. 23, 11770–11777 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gong, B. et al. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J. Clin. Invest. 114, 1624–1634 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Conti, M. et al. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J. Biol. Chem. 278, 5493–5496 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Robichaud, A. et al. Deletion of phosphodiesterase 4D in mice shortens 2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J. Clin. Invest. 110, 1045–1052 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kalgutkar, A. S., Choo, E., Taylor, T. J. & Marfat, A. Disposition of CP-671,305, a selective phosphodiesterase 4 inhibitor in preclinical species. Xenobiotica 34, 755–770 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Ahmed, T. & Frey, J. U. Expression of the specific type IV phosphodiesterase gene PDE4B3 during different phases of LTP in single hippocampal slices of rats in vitro. Neuroscience 117, 627–638 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Miro, X., Perez-Torres, S., Palacios, J. M., Puigdomenech, P. & Mengod, G. Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs. Synapse 40, 201–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Sasaki, T., Kotera, J. & Omori, K. Novel alternative splice variants of rat phosphodiesterase 7B showing unique tissue-specific expression and phosphorylation. Biochem. J. 361, 211–220 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Reyes-Irisarri, E., Perez, S. & Mengod, G. Neuronal expression of cAMP-specific phosphodiesterase 7B in the rat brain. Neuroscience 132, 1173–1185 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Sasaki, T., Kotera, J. & Omori, K. Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. J. Neurochem. 89, 474–483 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Perez-Torres, S. et al. Alteration of phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization. Exp. Neurol. 182, 322–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Sasaki, T., Yuasa, K. & Omori, K. Identification of human PDE7B, a cAMP specific phosphodiesterase. Biochem. Biophys. Res. Comm. 271, 575–583 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Gardner, C., Robas, N., Cawkill, D. & Fidock, M. Cloning and characterization of the human and mouse PDE7B, a novel cAMP-specific cyclic nucleotide phosphodiesterase. Biochem. Biophys. Res. Comm. 272, 186–192 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Barnes, M. J. et al. Synthesis and structure–activity relationships of guanine analogues as phosphodiesterase 7 (PDE7) inhibitors. Bioorg. Med. Chem. Lett. 11, 1081–1083 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Pitts, W. J. et al. Identification of purine inhibitors of phosphodiesterase 7 (PDE7). Bioorg. Med. Chem. Lett. 14, 2955–2958 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Vergne, F. et al. Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: design, synthesis and structure–activity relationship studies. Bioorg. Med. Chem. Lett. 14, 4607–4613 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Kobayashi, T. et al. Molecular comparison of rat cyclic nucleotide phosphodiesterase 8 family: unique expression of PDE8B in rat brain. Gene 319, 221–231 (2003).

    Article  CAS  Google Scholar 

  49. Prickaerts, J. et al. Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience 113, 351–361 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Prickaerts, J. et al. Phosphodiesterase type 5 inhibition improves early memory consolidation of object information. Neurochem. Int. 45, 915–928 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Devan, B. D. et al. Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats. Pharmacol. Biochem. Behav. 79, 691–699 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Kotera, J. et al. Expression of rat cGMP-binding cGMP-specific phosphodiesterase mRNA in Purkinje cell layers during postnatal neuronal development. Eur. J. Biochem. 249, 434–442 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Kotera, J., Fujishige, K. & Omori, K. Immunohistochemical localization of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in rat tissues. J. Histochem. Cytochem. 48, 685–693 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Rapoport, M., van Reekum, R. & Mayberg, H. The role of the cerebellum in cognition and behavior. J. Neuropsychiatry Clin. Neurosci. 12, 193–198 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Hartell, N. A. Inhibition of cGMP breakdown promotes the induction of cerebellar long-term depression. J. Neurosci. 16, 2881–2890 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. van Staveren, W. C. et al. Cloning and localization of the cGMP-specific phosphodiesterase type 9 in the rat brain. J. Neurocytol. 31, 729–741 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Schultheiss, D. et al. Central effects of sildenafil (Viagra) on auditory selective attention and verbal recognition memory in humans: a study with event-related brain potentials. World J. Urol. 19, 46–50 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Andreeva, S. G., Dikkes, P., Epstein, P. M. & Rosenberg, P. A. Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain. J. Neurosci. 21, 9068–9076 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Guipponi, M. et al. Identification and characterization of a novel cyclic nucleotide phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing of mRNA transcripts, genomic structure and sequence. Hum. Genet. 103, 386–392 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Straub, R. E. et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nature Genet. 8, 291–296 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Detera-Wadleigh, S. D. et al. Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q. Am. J. Hum. Genet. 58, 1279–1285 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gurling, H. Chromosome 21 workshop. Psychiatr. Genet. 8, 109–113 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Wunder, F. et al. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol. Pharm. 68, 1775–1781 (2005).

    CAS  Google Scholar 

  64. Sonnenburg, W. K., Mullaney, P. J. & Beavo, J. A. Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. J. Biol. Chem. 266, 17655–17661 (1991).

    CAS  PubMed  Google Scholar 

  65. Martins, T. J., Mumby, M. C. & Beavo, J. A. Purification and characterization of a cyclic nucleotide GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J. Biol. Chem. 257, 1973–1979 (1982).

    CAS  PubMed  Google Scholar 

  66. Repaske, D. R., Corbin, J. G., Conti, M. & Goy, M. F. A cyclic GMP-stimulated cyclic nucleotide phosphodiesterase gene is highly expressed in the limbic system of the rat brain. Neuroscience 56, 673–686 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Juilfs, D. M. et al. A subset of olfactory neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory transduction pathway. Proc. Natl Acad. Sci. USA 94, 3388–3395 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Meyer, M. R., Angele, A., Kremme, E., Kaupp, U. B. & Muller, F. A cGMP-signaling pathway in a subset of olfactory sensory neurons. Proc. Natl Acad. Sci. USA 97, 10595–10600 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Coleman, R. W. Platelet cyclic adenosine monophosphate phosphodiesterases: targets for regulating platelet-related thrombosis. Semin. Thromb. Hemost. 30, 451–460 (2004).

    Article  Google Scholar 

  70. Velardez, M. O. et al. Role of phosphodiesterase and protein kinase G on nitric oxide-induced inhibition of prolactin release from the rat anterior pituitary. Eur. J. Endocrinol. 143, 279–284 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Suvarna, N. U. & O'Donnell, J. M. Hydrolysis of N-methyl-D-aspartate receptor stimulated cAMP and cGMP by PDE4 and PDE2 phosphodiesterases in primary neuronal cultures of rat cerebral cortex and hippocampus. J. Pharmacol. Exp. Ther. 302, 249–256 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Boess, F. G. et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47, 1081–1092 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Strick, C. A., Schmidt, C. J. & Menniti, F. S. in Phosphodiesterases in Health and Disease (eds Francis, S., Houslay, M. & Beavo, J.) (CRC, London 2006).

    Google Scholar 

  74. Soderling, S. H., Bayuga, S. J. & Beavo, J. A. Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc. Natl Acad. Sci. USA 96, 7071–7076 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Loughney, K. et al. Isolation and characterization of PDE10A, a novel human 3′,5'-cyclic nucleotide phosphodiesterase. Gene 234, 109–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Fujishige, K., Kotera, J. & Omori, K. Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur. J. Biochem. 266, 1118–1127 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Seeger, T. F. et al. Immunohistochemical localization of PDE10A in the rat brain. Brain Res. 985, 113–126 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Graybiel, A. M. The basal ganglia. Curr. Biol. 10, R509–R511 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Siuciak, J. A. et al. Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Neuropharmacology 6 June 2006 [epub ahead of print].

  80. Siuciak, J. A. et al. Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 14 June 2006 [epub ahead of print].

  81. O'Connor, V. et al. Differential amplification of intron-containing transcripts reveals long term potentiation-associated up-regulation of specific Pde10A phosphodiesterase splice variants. J. Biol. Chem. 279, 15841–15849 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Jeon, Y. H. et al. Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cell. Mol. Life Sci. 62, 1198–1220 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, H., Liu, Y., Chen, Y., Robinson, H. & Ke, H. Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. J. Biol. Chem. 280, 30949–30955 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Ecker, G. F. & Noe, C. R. In silico prediction models for blood–brain barrier permeation. Curr. Med. Chem. 11, 1617–1628 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Fromm, M. F. Importance of P-glycoprotein at blood–tissue barriers. Trends Pharmacol. Sci. 25, 423–429 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Noridner, U. & Haeberlein, M. Computational approaches to the prediction of blood–brain distribution. Adv. Drug Deliv. Rev. 54, 291–313 (2002).

    Article  Google Scholar 

  87. Clark, D. E. Rapid calculation of polar molecular surface area and its application to predict transport phenomena. 2. Prediction of blood–brain barrier penetration. J. Pharm. Sci. 88, 815–821 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Card, G. L. et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 12, 2233–2247 (2004). In-depth analysis of the structure of the PDEs derived from X-ray crystallography and how this information informs the drug discovery process.

    Article  CAS  PubMed  Google Scholar 

  89. Seelig, A. A general pattern for substrate recognition by P-glycoprotein. Eur. J. Biochem. 251, 252–261 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Pajeva, I. K. & Wiese, M. Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis). J. Med. Chem. 45, 5671–5686 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Rotella, D. P. Phosphodiesterase 5 inhibitors: current status and potential applications. Nature Rev. Drug Discov. 1, 674–682 (2002).

    Article  CAS  Google Scholar 

  92. Padma-Nathan, H. Efficacy and tolerability of Tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. Am. J. Cardiol. 92 (Suppl.) 19M–25M (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Barnes, P. J. New drugs for asthma. Nature Rev. Drug Discov. 3, 831–844 (2004).

    Article  CAS  Google Scholar 

  94. Dyke, H. J. & Montana, J. G. Update of the therapeutic potential of PDE4 inhibitors. Expert Opin. Investig. Drugs 11, 1–13 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Lipworth, B. J. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365, 167–175 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Snyder, P. B., Esselstyn, J. M., Loughney, K., Wolda, S. L. & Florio, V. A. The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J. Lipid Res. 46, 494–503 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Chambers, R. J. et al. A new chemical tool for exploring the physiological function of the PDE2 isozyme. Bioorg. Med. Chem. Lett. 16, 307–310 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Shakur, Y. et al. Membrane localization of cyclic nucleotide phosphodiesterase 3 (PDE3). J. Biol. Chem. 275, 38749–38761 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Reinhardt, R. R. & Bondy, C. A. Differential cellular pattern of gene expression for two distinct cGMP-inhibited cyclic nucleotide phosphodiesterases in developing and mature rat brain. Neuroscience 72, 567–578 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. Lin, C. S. Tissue expression, distribution and regulation of PDE5. Int. J. Impot. Res. 16, S8–S10 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Pfizer Global Research and Development, CNS Discovery, Groton, 06340, Connecticut, USA

    Frank S. Menniti & Christopher J. Schmidt

  2. Pfizer Global Research and Development, Research Technology Centre, Cambridge, 02139, Massachusetts, USA

    W. Stephen Faraci

Authors
  1. Frank S. Menniti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Stephen Faraci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher J. Schmidt.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Menniti, F., Faraci, W. & Schmidt, C. Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5, 660–670 (2006). https://doi.org/10.1038/nrd2058

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2058

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing