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Physiological Activity of Phosphodiesterase
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Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current literature suggests that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. The clinical and commercial success of drugs like vinpocetine, nicardipine, cilostamide, milrinone, Cilostazol, rolipram, cilomilast, roflumilast, sildenafil, tadalafil, vardenafil, zaprinast, dipyridamole, papaverine have increased interest from pharmaceutical companies and academic researchers to further explore the hidden activities of phosphodiesterase activity and development of specific inhibitors of phosphodiesterase enzymes. PDE inhibitors are currently available or in development for treatment of a variety of disease conditions like depression, neurological functioning, Alzheimer's disease, parkinsonism, schizophrenia, asthma, COPD, allergic rhinitis, psoriasis, multiple sclerosis, inflammatory disease, cardiovascular diseases, pulmonary arterial hypertension. Thus PDEs serve as better drug target and current research advancements make them essential for the field of PDE research to develop more specific inhibitors at the level of different PDE sub-families and isoforms to overcome adverse effects nausea, headache, emesis, dizziness, flushing, dyspepsia, nasal congestion or rhinitis, vasodilation which are impediment for clinical approval.
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