Volume 200 of the series Handbook of Experimental Pharmacology pp 93-133


Inhibition of Cyclic Nucleotide Phosphodiesterases by Methylxanthines and Related Compounds

  • Sharron H. FrancisAffiliated withDepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine Email author 
  • , Konjeti R. SekharAffiliated withDepartment of Radiation Biology, Vanderbilt University School of Medicine
  • , Hengming KeAffiliated withDepartment of Biochemistry and Biophysics, University of North Carolina at Chapel Hill
  • , Jackie D. CorbinAffiliated withDepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine

* Final gross prices may vary according to local VAT.

Get Access


Naturally occurring methylxanthines were the first inhibitors of cyclic nucleotide (cN) phosphodiesterases (PDEs) to be discovered. To improve potency and specificity for inhibition of various PDEs in research and for treatment of diseases, thousands of compounds with related structures have now been synthesized. All known PDE inhibitors contain one or more rings that mimic the purine in the cN substrate and directly compete with cN for access to the catalytic site; this review focuses on inhibitors that contain a nucleus that is closely related to the xanthine ring of theophylline and caffeine and the purine ring of cNs. The specificity and potency of these compounds for blocking PDE action have been improved by appending groups at positions on the rings as well as by modification of the number and distribution of nitrogens and carbons in those rings. Several of these inhibitors are highly selective for particular PDEs; potent and largely selective PDE5 inhibitors are used clinically for treatment of erectile dysfunction [sildenafil (Viagra™), tadalafil (Cialis™) and vardenafil (Levitra™)] and pulmonary hypertension [sildenafil (Revatio™) and tadalafil (Adenocirca)]. Related compounds target other PDEs and show therapeutic promise for a number of maladies.


Phosphodiesterases Cyclic AMP Cyclic GMP Theophylline Xanthine Caffeine Phosphodiesterase inhibitors Caffeine in beverages and foods