Phosphodiesterases

Phosphodiesterases

1. PHOSPHO-DIESTERASES Bhagya Siripalli , Department of pharmacology, SVIPS

2. INTRODUCTION A  phosphodiesterase  ( PDE ) is an  enzyme  that breaks a  phosphodiester bond. Usually,  phosphodiesterase  refers to cyclic nucleotide phosphodiesterases. However, there are many other families of phosphodiesterases, including  phospholipases  C and D,  autotaxin ,  sphingomyelin phosphodiesterase ,  DNases ,  RNases , and restriction endonucleases (which all break the phosphodiester backbone of DNA or RNA), as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the  phosphodiester bond in the second messenger molecules  cAMP  and  cGMP . They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules.

3. PDE MAIN TISSUE LOCALIZATION 1 Brain, heart, vascular smooth muscle 2 Adrenal cortex, brain, heart, corpus cavernosum 3 Heart, corpus cavernosum, vascular smooth muscle, platelets, liver pancreas 4 Lung, mast cells, vascular smooth muscle 5 Corpus cavernosum, lung, vascular smooth muscle, platelets, brain, esophagus 6 Retina 7 Skeletal muscle, T cells 8 Testis, thyroid 9 Broadly expressed, not well characterized 10 Brain, testes 11 Skeletal muscle, prostate, liver, kidney, pituitary, testis

4. Drugs t h at b l o c k subtype s o f t h e enzyme phosphodiesterase (PDE). Therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). They are classified into non-selective PDE inhibitors and selective PDE.

5. A) Nonselective phosphodiesterase inhibitors

6. B) Selective phosphodiesterase inhibitors

7. PDE4 selective inhibitors Mesembrine, Rolipram, Ibudilast, Piclamilast, Luteolin, Drotaverine. PDE5 Inhibitors Sildenafil, Tadalafil, Vardenafil (10 times more potent than sildenafil) Udenafil , Avanafil, Lodenafil

8. Pharmacological effect of PDE inhibitors PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, dementia, depression, asthma, COPD,  protozoal infections (including malaria) and schizophrenia. PDE also are important in seizure incidence. For example, PDE compromised the antiepileptic activity of adenosine. In addition, using of a PDE inhibitor ( pentoxifylline ) in pentylenetetrazole -induced seizure indicated the antiepileptic effect by increasing the time latency to seizure incidence and decreasing the seizure duration in vivo. Cilostazol  ( Pletal ) inhibits PDE3. This inhibition allows red blood cells to be more able to bend. This is useful in conditions such as intermittent claudication , as the cells can maneuver through constricted veins and arteries more easily.

9. Dipyridamole inhibits PDE-3 and PDE-5. This leads to intraplatelet accumulation of cAMP and/or cGMP , inhibiting platelet aggregation. Zaprinast  inhibits the growth of asexual blood-stage malaria parasites ( P. falciparum )  in vitro  with an ED 50  value of 35 μM , and inhibits PfPDE1, a  P. falciparum cGMP -specific phosphodiesterase , with an IC 50  value of 3.8 μM . Xanthines  such as caffeine and  theobromine  are  cAMP-phosphodiesterase inhibitors. However, the inhibitory effect of xanthines on phosphodiesterases are only seen at dosages higher than what people normally consume. Sildenafil ,  Tadalafil and  Vardenafil  are PDE-5 inhibitors and are widely used in the treatment of erectile dysfunction. Pharmacological effect of PDE inhibitors

10. Therapeutic roles

11. Clinical significance Phosphodiesterase enzymes have been shown to be different in different types of cells, including normal and leukemic lymphocytes and are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by  cAMP  or  cGMP  by inhibition of their degradation by PDE. Sildenafil  (Viagra) is an inhibitor of  cGMP -specific phosphodiesterase type 5, which enhances the vasodilatory effects of cGMP in the corpus cavernosum  and is used to treat erectile dysfunction. Sildenafil is also currently being investigated for its myo - and cardioprotective effects, with particular interest being given to the compound's therapeutic value in the treatment of  Duchenne muscular dystrophy and benign prostatic hyperplasia. Paraxanthine , the main metabolite of caffeine, is another cGMP -specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase . PDE9 is expressed as high as PDE5 in the corpus cavernosum .