International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304 Vol.1, No.4, pp 1148-1160, Oct-Dec 2009 PHOSPHODIESTERASE INHIBITORS: THEIR ROLE AND IMPLICATIONS Rumi Ghosh*1, Onkar Sawant 1, Priya Ganpathy1, Shweta Pitre1 and V.J.Kadam1 1Dept. of Pharmacology ,Bharati Vidyapeeth’s College of Pharmacy, University of Mumbai, Sector 8, CBD Belapur, Navi Mumbai -400614, India. *Corres.author: rumi 1968@ hotmail.com ABSTRACT: Phosphodiesterase (PDE) isoenzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and thus have pivotal roles in cellular functions. PDE inhibitors such as theophylline have been employed as anti-asthmatics since decades and numerous novel selective PDE inhibitors are currently being investigated for the treatment of diseases such as Alzheimer’s disease, erectile dysfunction and many others. This review attempts to elucidate the pharmacology, applications and recent developments in research on PDE inhibitors as pharmacological agents. Keywords: Phosphodiesterases, Phosphodiesterase inhibitors. INTRODUCTION Alzheimer’s disease, COPD and other aliments. By cAMP and cGMP are intracellular second messengers inhibiting specifically the up-regulated PDE isozyme(s) involved in the transduction of various physiologic with newly synthesized potent and isoezyme selective stimuli and regulation of multiple physiological PDE inhibitors, it may possible to restore normal processes, including vascular resistance, cardiac output, intracellular signaling selectively, providing therapy with visceral motility, immune response (1), inflammation (2), reduced adverse effects (9). neuroplasticity, vision (3), and reproduction (4). Intracellular levels of these cyclic nucleotide second AN OVERVIEW OF THE PHOSPHODIESTERASE messengers are regulated predominantly by the complex SUPER FAMILY superfamily of cyclic nucleotide phosphodiesterase The PDE super family is large, complex and represents (PDE) enzymes. Cyclic nucleotide phosphodiesterases 11 gene families (PDE1 through PDE11). Each of the (PDEs) comprise a superfamily of metallophospho- PDE families contains one to four genes, and many genes hydrolases that specifically cleave the 3′, 5′-cyclic generate multiple isoforms. All the members of the PDE phosphate moiety of cAMP and/or cGMP to produce the superfamily differ in various aspects such as localization corresponding 5′-nucleotide. PDEs are critical or tissue distribution, mode of regulation and inhibitor determinants for modulation of cellular levels of cAMP specificity (6). The PDES are found in the cytosol, plasma and/or cGMP by many stimuli (10) .Thus, the ubiquitously membranes, endoplasmic reticulum, nuclear membranes present PDEs play a pivotal role in regulating cell and the cytoskeleton (7, 8). PDEs are regulated by signalling via the breakdown of cAMP and cGMP (5). intracellular cyclic nucleotide concentrations, PDE inhibitors are therapeutic agents which phosphorylation, interaction with regulatory proteins, target PDE isoenzymes and inhibit the metabolism of the subcellular compartmentalization, and binding of secondary messengers (cAMP, cGMP) thus, prolonging Ca2þ/calmodulin, as well as by changes in gene the biological effect determined by the type of cell expression (6). PDE3, PDE4, and PDE7 and PDE8 involved. hydrolyze only cAMP (cAMP-PDE). PDE5, PDE6 and PDE9 hydrolyze only cGMP (cGMP-PDE), and isozymes Both non selective and selective inhibitors of PDE are PDE1 and PDE2 accept both nucleotides as a substrate (6, currently being explored as possible treatments for a 12). variety of conditions such as sexual dysfunction, Rumi Ghosh et al /Int.J. PharmTech Res.2009,1(4) 1149 Table 1: Phosphodiesterases superfamily (6, 9) PDE SUBSTRATE REGULATIONS INHIBITORS CLINICAL FAMILY APPLICATIONS PDE 1 cAMP/cGMP Ca2þ/calmodulin activated Vinpocetine Dementia, memory loss Nicardipine 8-MeOM-IBMX Nimodipine PDE 2 cAMP/cGMP Stimulated/ activated by EHNA Sepsis cGMP Acute respiratory distress syndrome Memory loss PDE 3 cAMP/cGMP cGMP-inhibited Lixazinone Glomerulonephritis Cilostamide Congestive heart failure Milrinone Intermittent claudication Cilostazol Thrombosis Dihydro-pyridazinone Pulmonary hypertension PDE 4 cAMP cGMP-insensitive. Rolipram Glomerulonephritis Phosphorylated by PKA Denbufylline Asthma, COPD a Phosphorylated by ERK Cilomilast Bipolar depression Roflumilast Autoimmune encephalomyelitis Organ transplantation PDE 5 cGMP PKA/PKGphosphorylated Sildenafil (Viagra) Chronic renal failure Binds cGMP Zaprinast Salt retention in nephritic Dipyridamole syndrome Ariflo Pulmonary hypertension Vardenafil Erectile dysfunction Tadalafil Organ transplantation PDE 6 cGMP Transducin-activated Zaprinast Selective PDE6 Dipyridamole inhibitors are few and Vardenafil have little applications Tadalafil due to adverse effects on vission. PDE 7 cAMP Rolipram-insensitive Dipyridamole Airway and Thiadiazole immunological diseases. PDE 8 cAMP Rolipram-insensitive Dipyridamole Immunological IBMX-insensitive applications. PDE 9 cGMP IBMX-insensitive Zaprinast Possible hypoglycemic effects PDE 10 cAMP/cGMP Unknown Dipyridamole Treatment of Papaverine Schizophrenia and other neuro-pyschiatric disorders. PDE 11 cAMP/cGMP Unknown Tadalafil Proposed improvement Zaprinast of human testicular Dipyridamole functions. Rumi Ghosh et al /Int.J. PharmTech Res.2009,1(4) 1150 Fig1: General scheme of cyclic 3',5'-nucleotide metabolism (12). regulatory region between the amino acid terminal and · General structure of phosphodiesterases the catalytic core and lastly an amino acid terminal which isoenzyme. imparts isoform specificity. In particular, the size of the The general structure of the PDE super family consists N-terminal domain is substantially different in various of the basic features which include a catalytic core, PDE types. Fig 2: General Structure. Abbreviations: PKA, protein kinase A; PKG, protein kinase G; PKC, protein kinase C; PDE3IK, insulin-dependent PDE3B protein kinase(12) Rumi Ghosh et al /Int.J. PharmTech Res.2009,1(4) 1151 PHOSPHODIESTERASE AND ITS INHIBITORS to its putative inhibition of smooth muscle cell 1. PDE1 and its inhibitors proliferation, an event that contributes importantly to the Overview: pathophysiology of atherosclerosis. Other likely roles of The PDE1 family was the first eluted fraction isolated by PDE1C are in olfaction, regulation of sperm function and chromatography from vascular smooth muscle. This neuronal signaling (15). PDE1 fraction was specifically activated by Ca2+/CaM, and thus named CaM-PDE ( Calcium calmodulin PDE1 inhibitors: dependent PDE) (13). The cooperative binding of four Vinpocetine (Brand names: Cavinton, Intelectol; Ca2+ to calmodulin is required to fully activate CaM-PDE Chemical name: ethyl apovincaminate) (14). Three genes (PDE1A, PDE1B,and PDE1C) with Vinpocetine is a semisynthetic derivative of vincamine, various splice variants constitute PDE1 family. These which is extracted from the periwinkle plant. It increases soluble enzymes are homodimerics. In this unique CaM- cerebral blood flow and is said to improve memory.It is -5 sensitive PDE family, sensitivity to calcium and an inhibitor of PDE1 with an IC50 of approximately 10 calmodulin varies from one variant to the other. (16,17). M. The substance is widely sold as a supplement. However, there appears to be some controversy over the Localization and distribution: possibility of adverse reaction, and so in some cases low Most PDE1s are cytosolic; however there are instances of initial dose is recommended. There is also an isolated some being localized to sub cellular regions.PDE1A is claim of agranulocytosis (15).Vinpocetine is included in highly expressed in the brain. In human spermatozoa, many performance-enhancing supplements to improve PDE1A is tightly associated to calmodulin and is delivery of nutrients to muscles after physical workouts. permanently activated (18). Phosphodiesterases (PDEs) have come into focus as interesting potential targets for PDE inhibitor-based anti- PDE1B1 mRNA is found predominantly in the human parasitic drugs, Genomes of the various agents of human brain at the level of neuronal cells of the cerebellum, malaria, most notably Plasmodium falciparum, all hippocampus, caudate, and Purkinje cells, its expression contain four genes for class 1 PDEs, hinting PDE1 as is correlated with brain regions having extensive possible anti-malarial targets(91).Recently, a new PDE1 dopaminergic innervation and D1 dopamine receptor inhibitor, IC224 , was developed by ICOS Corporation mRNA (19). PDE1B1 is also found in the heart and (29). According to these few data, if IC224 similarly skeletal muscle (20). inhibits basal and calmodulin-activated PDE1 subtypes, PDE1C1 mRNA is mainly expressed in the brain and the this compound would be very helpful to characterize heart (20) and seems to be the major type highly expressed PDE1 activity and to clearly investigate the various roles in the mouse cerebellar granular cells (21). PDE1C2 of PDE1 in pathophysiology. represents the high-affinity CaM-PDE in olfactory epithelium (22) and PDE1C1 and PDE1C4/5 mRNA are 2. PDE2 and its inhibitors present in the testis (21). Overview: The PDE2 family is encoded by a single gene (PDE2A) Pharmacology: and has three splice variants, PDE2A1, PDE2A2, and PDE1 has been implicated to play a role in a number of PDE2A3. PDE2 enzymes are mainly purified from physiological and pathological processes. PDE1A most bovine hearts, adrenal tissues and brain cortex and likely