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Phosphodiesterases A phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. 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 (cellular level)amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules. There are 11 subtypes of PDEs, named PDE1-11; PDE4, 7 and 8 selectively degrade cAMP, PDE5, 6 and 9 selectively degrade cGMP and PDE1, 2, 3, 10 and 11 degrade both cyclic nucleotides( with over 50 isotypes). PDEs are expressed ubiquitously, with each subtype having a specific tissue distribution. These enzymes are involved in many signal transduction pathways and their functions include vascular smooth muscle proliferation and contraction, cardiac contractility, platelet aggregation, hormone secretion, immune cell activation, and they are involved in learning and memory. PDE 1 2 3 4 5 6 7 8 9 10 11 Main tissue localization Brain , Haert,Vascular smooth muscle. Adrenal cortex, Brain, Haert , Corpus covernosum. Haert , Corpus covernosum, Vascular smooth muscle, platelets, liver, pancreas. Lung, Mast cell, Vascular smooth muscle. Haert, Corpus covernosum, Vascular smooth muscle, platelets,Brain, esophagus. Retina. Skeletal Muscle, T cell. Testis, Thyroid. Broadly expressed, not well characterized. Brain , Testes. Skeletal Muscle, Prostate,Liver, Kidny, Pitutary,Testis Phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). Classification They are classified into selective and nonselective phosphodiesterase inhibitors Nonselective phosphodiesterase inhibitors Methylated xanthines and derivatives: caffeine, a minor stimulant aminophylline IBMX (3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research paraxanthine pentoxifylline, a drug that has the potential to enhance circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries theobromine theophylline, a bronchodilator Methylated xanthines act as both competitive nonselective phosphodiesterase inhibitors, which raise intracellular cAMP, activate PKA, inhibit TNF-alpha and leukotriene synthesis, and reduce inflammation and innate immunity and nonselective adenosine receptor antagonists selective phosphodiesterase inhibitors PDE1 selective inhibitors Vinpocetine PDE2 selective inhibitors BAY 60-7550 (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one) Oxindole EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine) PDE3 selective inhibitors Milrinone and Enoximone are used clinically for short-term treatment of cardiac failure. These drugs mimic sympathetic stimulation and increase cardiac output. Anagrelide Cilostazol is used in the treatment of intermittent claudication. Pimobendan is FDA approved for veterinary use in the treatment of heart failure in animals. PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. PDE4 selective inhibitors Mesembrine, Rolipram, Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose. Piclamilast,Luteolin, Drotaverine, used to alleviate renal colic pain, also to hasten cervical dilatation in labor Roflumilast, indicated for people with severe COPD to prevent symptoms such as coughing and excess mucus from worsening[ PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD, and rhinitis. They suppress the release of cytokines and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects and have also recently been proposed for use as antipsychotics.[28][29] On October 26, 2009, The University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 (and therefore decreased levels of cAMP) in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to Hippocampusbased memory functions PDE5 selective inhibitors PDE5 has only one subtype, PDE5A, of which there are 4 isoforms in humans called PDE5A1-4. PDE5 enzyme is specific for cGMP which means it only hydrolyzes cGMP but not cAMP, the selectivity is mediated through network of hydrogen bonding which is favorable for cGMP but unfavorable for cAMP in PDE5. PDE5 is responsible for the degradation of cGMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis, which leads to erectile dysfunction (ED). Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, in the corpus cavernosum. are used primarily for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension. Dipyridamole also inhibits PDE5. This results in added benefit when given together with NO or statins. Claimed newer and more-selective inhibitors are icariin. PDE7 selective inhibitors Recently, quinazoline type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents PDE10 selective inhibitors Papaverine, an opium alkaloid, PDE10 inhibitor, in the striatum and subsequent increase in cAMP and cGMP. Papaverine) is "a novel therapeutic in the discovery of antipsychotics". ==========================================================