Abstract

Phosphodiesterases (PDEs) are enzymes whose primary function is to terminate signaling of cyclic nucleotides by catalyzing the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) respectively. Invariably, these enzymes are considered to be critical regulators of the intracellular concentrations of cAMP and cGMP including their signaling pathways and accompanied biological effects. The levels of these cyclic nucleotides are maintained through a balance between production (done by adenyl cyclase and guanyl cyclase from adenosine triphosphate and guanosine triphosphate, respectively) and breakdown, (carried out by phosphodiesterases) resulting in the formation of the inactive forms 5’AMP and 5’GMP respectively. A number of extracellular stimuli, namely cytokines, light, growth factors, neurotransmitters and peptide hormones are generators of these signals to be carried by cyclic nucleotides. Cyclic nucleotides (signal-transducing molecules) modulate a number of biological processes, including apoptosis, myocardial contractility, platelet aggregation, proliferation and vascular smooth muscle relaxation. Various therapeutic agents block the unique phosphodiesterases function by increasing cyclic nucleotide concentration levels. In the present article, general information of phosphodiesterases will be given as well as presentation of a number of chemical compounds that target these enzymes.

Keywords: Phosphodiesterases; Phosphodiesterases Antagonists; Biological Activities

References

1. Francis SH., et al. “Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions”. Physiology Review 91 (2011): 651-690.
2. Bender AT. “Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use”. Pharmacology Review 58 (2006): 488-520.
3. Puzzo D., et al. “Role of phosphodiesterase 5 in synaptic plasticity and memory”. Neuropsychiatric Dis Treatment2 (2002): 371-387.
4. Lefièvre L., et al. “Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa”. Biology Reproduction 67 (2002): 423-430.
5. Deng C., et al. “Assays for cyclic nucleotide- phosphodiesterases (PDEs) in the central nervous system”. Current Protocol Neuroscience 7 (2007): 7-12.
6. Ahmad F., et al. “Cyclic nucleotide phosphodiesterase 3 signaling complexes”. Hormone Metabolism Research 44 (2012): 776-785.
7. Santos-Silva AJ., et al. “PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries”. European Journal Pharmacology 582 (2008): 102-109.
8. Omori K and Kotera J. “Overview of PDEs and their regulation”. Circulation Research 100 (2007): 309-327.
9. Francis SH., et al. “Phosphodiesterase inhibitors: factors that influence potency, selectivity, and action”. In Phosphodiesterases as Drug Targets; Springer: Berlin/Heidelberg, Germany (2011): 47-84.
10. Beavo JA., et al. “Multiple cyclic nucleotide phosphodiesterases”. Molecular Pharmacology 46 (1994): 399-405.
11. Yan C., et al. “The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally dierent splice variants in a tissue-specific manner”. Journal Biology Chemistry 271 (1996): 25699-25706.
12. Fidock M., et al. “Isolation and differential tissue distribution of two human cDNAs encoding PDE1 splice variants”. Cell Signal 14 (2002): 53-60.
13. Hamet P and Coquil JF. “Cyclic GMP binding and cyclic GMP phosphodiesterase in rat platelets”. Journal Cyclic Nucleotide Research 4 (1978):281-290.
14. Lin CS., et al. “Expression of three isoforms of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in human penile cavernosum”. Biochemistry Biophysic Research Communication 268 (2000): 628-635.
15. Witwicka H., et al. “Hydrolysis of cyclic GMP in rat peritoneal macrophages”. Acta Biochimica Polonica 49 (2002): 891-897.
16. Andreeva SG., et al. “Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain”. Journal Neuroscience 21 (2001): 9068-9076.
17. Fujishige K and Kotera J. “Striatum and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A”. European Journal Biochemistry 266 (1999): 1118-1127.
18. Francis SH., et al. “Inhibition of cyclic nucleotide phosphodiesterases by methylxanthines and related compounds”. Handbook Experimental Pharmacology 200 (2011): 93-133.
19. Keravis T and Lugnier C. “Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments”. British Journal Pharmacology 165 (2012):1288-1305.
20. Medina AE. “Vinpocetine as a potent antiinflammatory agent”. Proceedings National Academy Sciences USA 107 (2010): 9921-9922.
21. Boswell-Smith V., et al. “Phosphodiesterase inhibitors”. British Journal Pharmacology1 (2006): S252-S257.
22. Wynands JE. “The role of amrinone in treating heart failure during and after coronary artery surgery supported by cardiopulmonary bypass”. Journal Cardiac Surgery 9 (1994): 453-458.
23. Kishi Y., et al. “Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall”. Cardiovascular Drug Review 19 (2001): 215-225.
24. Giembycz MA. “Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease”. Proceedings American Thoracic Society 2 (2005): 326-231.
25. Staord GI., et al. “Review on plants with CNS-effects used in traditional South African medicine against mental diseases”. Journal Ethnopharmacology 119 (2008): 513-537.
26. Vellas B., et al. “EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study”. Current Alzheimer Research 8 (2011): 203-212.
27. Diamant Z and Spina D. “PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease”. Pulmonary Pharmacology Therapeutics 24 (2011): 353-360.
28. Mangas A., et al. “New drug therapies for multiple sclerosis”. Current Opinion Neurology.23 (2010): 287-292.
29. Kulkarni SK and Patil CS. “Phosphodiesterase 5 enzyme and its inhibitors: update on pharmacological and therapeutical aspects”. Methods Findings Experimental Clinical Pharmacology 26 (2004): 789-799.
30. Oudiz RJ., et al. “Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study”. Journal American Colloid Cardiology 60 (2012): 768-774.
31. Ding H and Du W., et al. “Efficacy and safety of udenafil for erectile dysfunction: a meta-analysis of randomized controlled trials”. Urology 80 (2012): 134-139.
32. D'Esterre CD and Lee TY. “Effect of dipyridamole during acute stroke: exploring antithrombosis and neuroprotective benefits”. Annals of the New York Academy of Sciences 1207 (2010): 71-75.
33. Lugnier C. “PDE inhibitors: a new approach to treat metabolic syndrome”. Current Opinion Pharmacology 11 (2011): 698-706.
34. Weeeks JI., et al. “Radiolabled ligand binding to the catalytic or allosteric sites of PDE 5 and PDE 11”. Methods Molecular Biology 307 (2005): 239-2662.