Phosphodiesterase 2 and Its Isoform A as Therapeutic Targets in the Central Nervous System Disorders.

Publisher: Bentham Science Publishers Country of Publication: United Arab Emirates NLM ID: 101269155 Publication Model: Print Cited Medium: Internet ISSN: 1996-3181 (Electronic) Linking ISSN: 18715273 NLM ISO Abbreviation: CNS Neurol Disord Drug Targets Subsets: MEDLINE

Original Publication: Saif Zone, Sharjah, U.A.E.; San Francisco, CA : Bentham Science Publishers, c2006-

Central Nervous System Diseases*/drug therapy ; Central Nervous System Diseases*/enzymology ; Cyclic Nucleotide Phosphodiesterases, Type 2*/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 2*/antagonists & inhibitors ; Phosphodiesterase Inhibitors*/therapeutic use ; Phosphodiesterase Inhibitors*/pharmacology; Animals ; Humans ; Cyclic AMP/metabolism ; Cyclic GMP/metabolism

Cyclic adenosine monophosphates (cAMP) and cyclic guanosine monophosphate (cGMP) are two essential second messengers, which are hydrolyzed by phosphodiesterase's (PDEs), such as PDE-2. Pharmacological inhibition of PDE-2 (PDE2A) in the central nervous system improves cAMP and cGMP signaling, which controls downstream proteins related to neuropsychiatric, neurodegenerative, and neurodevelopmental disorders. Considering that there are no specific treatments for these disorders, PDE-2 inhibitors' development has gained more attention in the recent decade. There is high demand for developing new-generation drugs targeting PDE2 for treating diseases in the central nervous and peripheral systems. This review summarizes the relationship between PDE-2 with neuropsychiatric, neurodegenerative, and neurodevelopmental disorders as well as its possible treatment, mainly involving inhibitors of PDE2.
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Azevedo M.F.; Faucz F.R.; Bimpaki E.; Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev 2014,35(2),195-233. (PMID: 10.1210/er.2013-105324311737)
Zhang C.; Lueptow L.M.; Zhang H.T.; O’Donnell J.M.; Xu Y.; The Role of Phosphodiesterase-2 in Psychiatric and Neurodegenerative Disorders. Adv Neurobiol 2017,17,307-347. (PMID: 10.1007/978-3-319-58811-7_1228956338)
Zhang C.; Yu Y.; Ruan L.; The roles of phosphodiesterase 2 in the central nervous and peripheral systems. Curr Pharm Des 2014,21(3),274-290. (PMID: 10.2174/138161282066614082611524525159070)
Steegborn C.; Structure, mechanism, and regulation of soluble adenylyl cyclases - similarities and differences to transmembrane adenylyl cyclases. Biochim Biophys Acta Mol Basis Dis 2014,1842(12)(12 Pt B),2535-2547. (PMID: 10.1016/j.bbadis.2014.08.01225193033)
Potter L.R.; Guanylyl cyclase structure, function and regulation. Cell Signal 2011,23(12),1921-1926. (PMID: 10.1016/j.cellsig.2011.09.00121914472)
Bender A.T.; Beavo J.A.; Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacol Rev 2006,58(3),488-520. (PMID: 10.1124/pr.58.3.516968949)
Conti M.; Beavo J.; Biochemistry and physiology of cyclic nucleotide phosphodiesterases: Essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007,76(1),481-511. (PMID: 10.1146/annurev.biochem.76.060305.15044417376027)
Feil S.; Zimmermann P.; Knorn A.; Distribution of cGMP-dependent protein kinase type I and its isoforms in the mouse brain and retina. Neuroscience 2005,135(3),863-868. (PMID: 10.1016/j.neuroscience.2005.06.05116154279)
Hofmann M.E.; Nahir B.; Frazier C.J.; Endocannabinoid-mediated depolarization-induced suppression of inhibition in hilar mossy cells of the rat dentate gyrus. J Neurophysiol 2006,96(5),2501-2512. (PMID: 10.1152/jn.00310.200616807350)
Kleppisch T.; Phosphodiesterases in the central nervous system. Handb Exp Pharmacol 2009,191(191),71-92. (PMID: 10.1007/978-3-540-68964-5_519089326)
Ashman D.F.; Lipton R.; Melicow M.M.; Price T.D.; Isolation of adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate from rat urine. Biochem Biophys Res Commun 1963,11(4),330-334. (PMID: 10.1016/0006-291X(63)90566-713965190)
Sonnenburg W.K.; Mullaney P.J.; Beavo J.A.; Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. J Biol Chem 1991,266(26),17655-17661. (PMID: 10.1016/S0021-9258(19)47421-81654333)
Yang Q.; Paskind M.; Bolger G.; A novel cyclic GMP stimulated phosphodiesterase from rat brain. Biochem Biophys Res Commun 1994,205(3),1850-1858. (PMID: 10.1006/bbrc.1994.28867811274)
Martins T.J.; Mumby M.C.; Beavo J.A.; Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J Biol Chem 1982,257(4),1973-1979. (PMID: 10.1016/S0021-9258(19)68134-26276403)
Huang D.; Hinds T.R.; Martinez S.E.; Doneanu C.; Beavo J.A.; Molecular determinants of cGMP binding to chicken cone photoreceptor phosphodiesterase. J Biol Chem 2004,279(46),48143-48151. (PMID: 10.1074/jbc.M40433820015331594)
Wu A.Y.; Tang X.B.; Martinez S.E.; Ikeda K.; Beavo J.A.; Molecular determinants for cyclic nucleotide binding to the regulatory domains of phosphodiesterase 2A. J Biol Chem 2004,279(36),37928-37938. (PMID: 10.1074/jbc.M40428720015210692)
Lugnier C.; Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents. Pharmacol Ther 2006,109(3),366-398. (PMID: 10.1016/j.pharmthera.2005.07.00316102838)
Gomez L.; Breitenbucher J.G.; PDE2 inhibition: Potential for the treatment of cognitive disorders. Bioorg Med Chem Lett 2013,23(24),6522-6527. (PMID: 10.1016/j.bmcl.2013.10.01424189054)
Stephenson D.T.; Coskran T.M.; Kelly M.P.; The distribution of phosphodiesterase 2A in the rat brain. Neuroscience 2012,226,145-155. (PMID: 10.1016/j.neuroscience.2012.09.01123000621)
Farmer R.; Burbano S.D.; Patel N.S.; Sarmiento A.; Smith A.J.; Kelly M.P.; Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease. Cell Signal 2020,70,109592. (PMID: 10.1016/j.cellsig.2020.10959232119913)
Gu G.; Scott T.; Yan Y.; Target engagement of a phosphodiesterase 2A inhibitor affecting long-term memory in the Rat. J Pharmacol Exp Ther 2019,370(3),399-407. (PMID: 10.1124/jpet.118.25585131253692)
Esteban J.A.; Shi S.H.; Wilson C.; Nuriya M.; Huganir R.L.; Malinow R.; PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat Neurosci 2003,6(2),136-143. (PMID: 10.1038/nn99712536214)
Akiyama H.; Fukuda T.; Tojima T.; Nikolaev V.O.; Kamiguchi H.; Cyclic nucleotide control of microtubule dynamics for axon guidance. J Neurosci 2016,36(20),5636-5649. (PMID: 10.1523/JNEUROSCI.3596-15.201627194341)
Crawford D.C.; Mennerick S.; Presynaptically silent synapses: Dormancy and awakening of presynaptic vesicle release. Neuroscientist 2012,18(3),216-223. (PMID: 10.1177/107385841141852521908849)
Kleppisch T.; Feil R.; cGMP signalling in the mammalian brain: Role in synaptic plasticity and behaviour. Handb Exp Pharmacol 2009,191(191),549-579. (PMID: 10.1007/978-3-540-68964-5_2419089345)
Averaimo S.; Nicol X.; Intermingled cAMP, cGMP and calcium spatiotemporal dynamics in developing neuronal circuits. Front Cell Neurosci 2014,8,376. (PMID: 10.3389/fncel.2014.0037625431549)
Stoufflet J.; Chaulet M.; Doulazmi M.; Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration. Sci Adv 2020,6(36),eaba3992. (PMID: 10.1126/sciadv.aba399232917588)
2022.
Chen C.N.; Denome S.; Davis R.L.; Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce+ gene, the structural gene for cAMP phosphodiesterase. Proc Natl Acad Sci USA 1986,83(24),9313-9317. (PMID: 10.1073/pnas.83.24.93133025834)
Repaske D.R.; Swinnen J.V.; Jin S.L.; Van Wyk J.J.; Conti M.; A polymerase chain reaction strategy to identify and clone cyclic nucleotide phosphodiesterase cDNAs. Molecular cloning of the cDNA encoding the 63-kDa calmodulin-dependent phosphodiesterase. J Biol Chem 1992,267(26),18683-18688. (PMID: 10.1016/S0021-9258(19)37015-21326532)
Martinez S.E.; Bruder S.; Schultz A.; Crystal structure of the tandem GAF domains from a cyanobacterial adenylyl cyclase: Modes of ligand binding and dimerization. Proc Natl Acad Sci USA 2005,102(8),3082-3087. (PMID: 10.1073/pnas.040991310215708973)
Kanacher T.; Schultz A.; Linder J.U.; Schultz J.E.; A GAF-domain-regulated adenylyl cyclase from Anabaena is a self-activating cAMP switch. EMBO J 2002,21(14),3672-3680. (PMID: 10.1093/emboj/cdf37512110580)
Ho Y.S.J.; Burden L.M.; Hurley J.H.; Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. EMBO J 2000,19(20),5288-5299. (PMID: 10.1093/emboj/19.20.528811032796)
Martinez S.E.; Beavo J.A.; Hol W.G.; GAF domains: Two-billion-year-old molecular switches that bind cyclic nucleotides. Mol Interv 2002,2(5),317-323. (PMID: 10.1124/mi.2.5.31714993386)
Pandit J.; Forman M.D.; Fennell K.F.; Dillman K.S.; Menniti F.S.; Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci USA 2009,106(43),18225-18230. (PMID: 10.1073/pnas.090763510619828435)
Yamamoto T.; Manganiello V.C.; Vaughan M.; Purification and characterization of cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from calf liver. Effects of divalent cations on activity. J Biol Chem 1983,258(20),12526-12533. (PMID: 10.1016/S0021-9258(17)44208-66313664)
Bender A.T.; Beavo J.A.; Specific localized expression of cGMP PDEs in Purkinje neurons and macrophages. Neurochem Int 2004,45(6),853-857. (PMID: 10.1016/j.neuint.2004.03.01515312979)
Sjöstedt E.; Zhong W.; Fagerberg L.; An atlas of the protein-coding genes in the human, pig, and mouse brain. Science 2020,367(6482),eaay5947. (PMID: 10.1126/science.aay594732139519)
Martinez S.E.; Wu A.Y.; Glavas N.A.; The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci USA 2002,99(20),13260-13265. (PMID: 10.1073/pnas.19237489912271124)
Zhu J.; Yang Q.; Dai D.; Huang Q.; X-ray crystal structure of phosphodiesterase 2 in complex with a highly selective, nanomolar inhibitor reveals a binding-induced pocket important for selectivity. J Am Chem Soc 2013,135(32),11708-11711. (PMID: 10.1021/ja404449g23899287)
Card G.L.; England B.P.; Suzuki Y.; Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 2004,12(12),2233-2247. (PMID: 10.1016/j.str.2004.10.00415576036)
Weber S.; Zeller M.; Guan K.; Wunder F.; Wagner M.; El-Armouche A.; PDE2 at the crossway between cAMP and cGMP signalling in the heart. Cell Signal 2017,38,76-84. (PMID: 10.1016/j.cellsig.2017.06.02028668721)
de Oliveira S.K.; Hoffmeister M.; Gambaryan S.; Müller-Esterl W.; Guimaraes J.A.; Smolenski A.P.; Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor. J Biol Chem 2007,282(18),13656-13663. (PMID: 10.1074/jbc.M61094220017329248)
Meyer M.R.; Angele A.; Kremmer E.; Kaupp U.B.; Müller F.; A cGMP-signaling pathway in a subset of olfactory sensory neurons. Proc Natl Acad Sci USA 2000,97(19),10595-10600. (PMID: 10.1073/pnas.97.19.1059510984544)
Colman R.W.; Platelet cyclic adenosine monophosphate phosphodiesterases: Targets for regulating platelet-related thrombosis. Semin Thromb Hemost 2004,30(4),451-460. (PMID: 10.1055/s-2004-83348015354266)
Velardez M.O.; De Laurentiis A.; del Carmen Díaz M.; Role of phosphodiesterase and protein kinase G on nitric oxide-induced inhibition of prolactin release from the rat anterior pituitary. Eur J Endocrinol 2000,143(2),279-284. (PMID: 10.1530/eje.0.143027910913949)
Suvarna N.U.; O’Donnell J.M.; Hydrolysis of N-methyl-D-aspartate receptor-stimulated cAMP and cGMP by PDE4 and PDE2 phosphodiesterases in primary neuronal cultures of rat cerebral cortex and hippocampus. J Pharmacol Exp Ther 2002,302(1),249-256. (PMID: 10.1124/jpet.302.1.24912065724)
Boess F.G.; Hendrix M.; van der Staay F.J.; Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 2004,47(7),1081-1092. (PMID: 10.1016/j.neuropharm.2004.07.04015555642)
Kumar A.; Sidhu J.; Goyal A.; Tsao J.W.; Alzheimer Disease 2022.
Murman D.; The Impact of Age on Cognition. Semin Hear 2015,36(3),111-121. (PMID: 10.1055/s-0035-155511527516712)
Murphy M.P.; LeVine H.; Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis 2010,19(1),311-323. (PMID: 10.3233/JAD-2010-122120061647)
Sanders O.; Rajagopal L.; Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale. J Alzheimers Dis Rep 2020,4(1),185-215. (PMID: 10.3233/ADR-20019132715279)
Ran I.; Laplante I.; Lacaille J.C.; CREB-dependent transcriptional control and quantal changes in persistent long-term potentiation in hippocampal interneurons. J Neurosci 2012,32(18),6335-6350. (PMID: 10.1523/JNEUROSCI.5463-11.201222553039)
Jehle A.; Garaschuk O.; The Interplay between cGMP and Calcium Signaling in Alzheimer’s Disease. Int J Mol Sci 2022,23(13),7048. (PMID: 10.3390/ijms2313704835806059)
Teich A.F.; Nicholls R.E.; Puzzo D.; Synaptic therapy in Alzheimer’s disease: A CREB-centric approach. Neurotherapeutics 2015,12(1),29-41. (PMID: 10.1007/s13311-014-0327-525575647)
Yiannopoulou K.G.; Papageorgiou S.G.; Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 2013,6(1),19-33. (PMID: 10.1177/175628561246167923277790)
Lueptow L.M.; Zhan C.G.; O’Donnell J.M.; Cyclic GMP–mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice. Psychopharmacology (Berl) 2016,233(3),447-456. (PMID: 10.1007/s00213-015-4129-126525565)
Nakashima M.; Suzuki N.; Shiraishi E.; Iwashita H.; TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models. Behav Brain Res 2019,376,112192. (PMID: 10.1016/j.bbr.2019.11219231521738)
Paes D.; Xie K.; Wheeler D.G.; Zook D.; Prickaerts J.; Peters M.; Inhibition of PDE2 and PDE4 synergistically improves memory consolidation processes. Neuropharmacology 2021,184,108414. (PMID: 10.1016/j.neuropharm.2020.10841433249120)
Jiang M.Y.; Han C.; Zhang C.; Discovery of effective phosphodiesterase 2 inhibitors with antioxidant activities for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2021,41,128016. (PMID: 10.1016/j.bmcl.2021.12801633838306)
Lees A.J.; Hardy J.; Revesz T.; Parkinson’s disease. Lancet 2009,373(9680),2055-2066. (PMID: 10.1016/S0140-6736(09)60492-X19524782)
Carlsson A.; Treatment of Parkinson’s with L-DOPA. The early discovery phase, and a comment on current problems. J Neural Transm (Vienna) 2002,109(5-6),777-787. (PMID: 10.1007/s00702020006412111467)
Pedrosa D.J.; Timmermann L.; Review: Management of Parkinson’s disease. Neuropsychiatr Dis Treat 2013,9,321-340. (PMID: 10.2147/NDT.S3230223487540)
Talati R.; Baker W.L.; Patel A.A.; Reinhart K.; Coleman C.I.; Adding a dopamine agonist to preexisting levodopa therapy vs. levodopa therapy alone in advanced Parkinson’s disease: A meta analysis. Int J Clin Pract 2009,63(4),613-623. (PMID: 10.1111/j.1742-1241.2009.02027.x19222614)
Vincent P.; Spitzer N.C.; Editorial: Dynamics of cyclic nucleotide signaling in neurons. Front Cell Neurosci 2015,9,296. (PMID: 10.3389/fncel.2015.0029626283926)
Hulley P.; Hartikka J.; Lübbert H.; Cyclic AMP promotes the survival of dopaminergic neurons in vitro and protects them from the toxic effects of MPP+. J Neural Transm Suppl 1995,46,217-228. (PMID: 8821058)
Wang Y.; Liu J.; Song G.; Yu Y.; Huang X.; Design and Synthesis of PDE2A Inhibitors for the Treatment of Parkinson’s Disease. ChemistrySelect 2022,7(36),e202202874. (PMID: 10.1002/slct.202202874)
Loh K.P.; Huang S.H.; De Silva R.; Tan B.K.; Zhu Y.Z.; Oxidative stress: Apoptosis in neuronal injury. Curr Alzheimer Res 2006,3(4),327-337. (PMID: 10.2174/15672050677824951517017863)
Klabnik J.; O’Donnell J.; Free Radic Biol Med. Curr Alzheimer Res 2011,50(10),1355-1367.
Lee D.H.; Heidecke H.; Schröder A.; Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease. Mol Neurodegener 2014,9(1),49. (PMID: 10.1186/1750-1326-9-4925398321)
Meyer L.S.; Gong S.; Reincke M.; Williams T.A.; Angiotensin I.I.; Angiotensin I.I.; Type 1 Receptor Autoantibodies in Primary Aldosteronism. Horm Metab Res 2020,52(6),379-385. (PMID: 10.1055/a-1120-864732168525)
Salpietro V.; Perez-Dueñas B.; Nakashima K.; A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. Mov Disord 2018,33(3),482-488. (PMID: 10.1002/mds.2728629392776)
Sharma S.R.; Gonda X.; Tarazi F.I.; Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacol Ther 2018,190,91-104. (PMID: 10.1016/j.pharmthera.2018.05.00729763648)
Chaste P.; Leboyer M.; Autism risk factors: Genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 2012,14(3),281-292. (PMID: 10.31887/DCNS.2012.14.3/pchaste23226953)
Hannon E.; Schendel D.; Ladd-Acosta C.; Elevated polygenic burden for autism is associated with differential DNA methylation at birth. Genome Med 2018,10(1),19. (PMID: 10.1186/s13073-018-0527-429587883)
Christensen J.; Grønborg T.K.; Sørensen M.J.; Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013,309(16),1696-1703. (PMID: 10.1001/jama.2013.227023613074)
Servadio M.; Melancia F.; Manduca A.; Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid. Transl Psychiatry 2016,6(9),e902. (PMID: 10.1038/tp.2016.18227676443)
Tartaglione A.M.; Schiavi S.; Calamandrei G.; Trezza V.; Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum disorder. Neuropharmacology 2019,159,107477. (PMID: 10.1016/j.neuropharm.2018.12.02430639388)
Song F.; Barton P.; Sleightholme V.; Yao G.; Fry-Smith A.; Screening for fragile X syndrome: A literature review and modelling study. Health Technol Assess 2003,7(16),1-106. (PMID: 10.3310/hta716012969542)
Hernandez R.N.; Feinberg R.L.; Vaurio R.; Passanante N.M.; Thompson R.E.; Kaufmann W.E.; Autism spectrum disorder in fragile X syndrome: A longitudinal evaluation. Am J Med Genet A 2009,149A(6),1125-1137. (PMID: 10.1002/ajmg.a.3284819441123)
Berry-Kravis E.M.; Harnett M.D.; Reines S.A.; Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: A randomized, placebo-controlled, phase 2 clinical trial. Nat Med 2021,27(5),862-870. (PMID: 10.1038/s41591-021-01321-w33927413)
De Rubeis S.; He X.; Goldberg A.P.; Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014,515(7526),209-215. (PMID: 10.1038/nature1377225363760)
Delhaye S.; Bardoni B.; Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders. Mol Psychiatry 2021,26(9),4570-4582. (PMID: 10.1038/s41380-020-00997-933414502)
Gurney M.E.; Nugent R.A.; Mo X.; Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders. J Med Chem 2019,62(10),4884-4901. (PMID: 10.1021/acs.jmedchem.9b0019331013090)
Schiavi S.; Carbone E.; Melancia F.; Phosphodiesterase 2A inhibition corrects the aberrant behavioral traits observed in genetic and environmental preclinical models of Autism Spectrum Disorder. Transl Psychiatry 2022,12(1),119. (PMID: 10.1038/s41398-022-01885-235338117)
Maurin T.; Melancia F.; Jarjat M.; Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome. Cereb Cortex 2019,29(8),3241-3252. (PMID: 10.1093/cercor/bhy19230137253)
Maurin T.; Lebrigand K.; Castagnola S.; HITS-CLIP in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein. Nucleic Acids Res 2018,46(12),6344-6355. (PMID: 10.1093/nar/gky26729668986)
Ding Q.; Zhang F.; Feng Y.; Wang H.; Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome. Int J Mol Sci 2020,21(23),9327. (PMID: 10.3390/ijms2123932733297570)
Foussias G.; Agid O.; Fervaha G.; Remington G.; Negative symptoms of schizophrenia: Clinical features, relevance to real world functioning and specificity versus other CNS disorders. Eur Neuropsychopharmacol 2014,24(5),693-709. (PMID: 10.1016/j.euroneuro.2013.10.01724275699)
Lin C.H.; Lane H.Y.; Tsai G.E.; Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav 2012,100(4),665-677. (PMID: 10.1016/j.pbb.2011.03.02321463651)
Hallak J.E.C.; Maia-de-Oliveira J.P.; Abrao J.; Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: A randomized, double-blind, placebo-controlled trial. JAMA Psychiatry 2013,70(7),668-676. (PMID: 10.1001/jamapsychiatry.2013.129223699763)
Ruan L.; Du K.; Tao M.; Phosphodiesterase-2 Inhibitor Bay 60-7550 Ameliorates Aβ-Induced Cognitive and Memory Impairment via Regulation of the HPA Axis. Front Cell Neurosci 2019,13,432. (PMID: 10.3389/fncel.2019.0043231632240)
Bollen E.; Akkerman S.; Puzzo D.; Object memory enhancement by combining sub-efficacious doses of specific phosphodiesterase inhibitors. Neuropharmacology 2015,95,361-366. (PMID: 10.1016/j.neuropharm.2015.04.00825896769)
Snyder G.L.; Vanover K.E.; PDE Inhibitors for the Treatment of Schizophrenia. Adv Neurobiol 2017,17,385-409. (PMID: 10.1007/978-3-319-58811-7_1428956340)
Nakashima M.; Imada H.; Shiraishi E.; Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N -Methyl-d-Aspartate Receptor Antagonist–Induced Rat Models of Schizophrenia. J Pharmacol Exp Ther 2018,365(1),179-188. (PMID: 10.1124/jpet.117.24550629440309)
Prickaerts J.; Heckman P.R.A.; Blokland A.; Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin Investig Drugs 2017,26(9),1033-1048. (PMID: 10.1080/13543784.2017.136436028772081)
Zhu M.J.; Shi J.; Chen Y.; Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior. Psychopharmacology (Berl) 2020,237(11),3215-3224. (PMID: 10.1007/s00213-019-05401-132926224)
Liu L.; Zheng J.; Huang X.F.; The neuroprotective and antidepressant-like effects of Hcyb1, a novel selective PDE2 inhibitor. CNS Neurosci Ther 2018,24(7),652-660. (PMID: 10.1111/cns.1286329704309)
Ding L.; Zhang C.; Masood A.; Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: Involvement of antioxidant and anti-apoptotic mechanisms. Behav Brain Res 2014,268,150-158. (PMID: 10.1016/j.bbr.2014.03.04224694839)
Huang X.; Xiaokaiti Y.; Yang J.; Inhibition of phosphodiesterase 2 reverses gp91phox oxidase-mediated depression- and anxiety-like behavior. Neuropharmacology 2018,143,176-185. (PMID: 10.1016/j.neuropharm.2018.09.03930268520)
Xu Y.; Pan J.; Chen L.; Phosphodiesterase-2 inhibitor reverses corticosterone-induced neurotoxicity and related behavioural changes via cGMP/PKG dependent pathway. Int J Neuropsychopharmacol 2013,16(4),835-847. (PMID: 10.1017/S146114571200065X22850435)
Mangot A.G.; Murthy V.S.; Psychiatric aspects of phosphodiesterases: An overview. Indian J Pharmacol 2015,47(6),594-599. (PMID: 10.4103/0253-7613.16959326729948)
de Vente J.; Markerink-van Ittersum M.; Vles J.S.H.; The role of phosphodiesterase isoforms 2, 5, and 9 in the regulation of NO-dependent and NO-independent cGMP production in the rat cervical spinal cord. J Chem Neuroanat 2006,31(4),275-303. (PMID: 10.1016/j.jchemneu.2006.02.00616621445)
Stephenson D.T.; Coskran T.M.; Wilhelms M.B.; Immunohistochemical localization of phosphodiesterase 2A in multiple mammalian species. J Histochem Cytochem 2009,57(10),933-949. (PMID: 10.1369/jhc.2009.95347119506089)
Wang J.; Wu M.; Lin X.; Li Y.; Fu Z.; Low-Concentration Oxygen/Ozone Treatment Attenuated Radiculitis and Mechanical Allodynia via PDE2A-cAMP/cGMP-NF- κ B/p65 Signaling in Chronic Radiculitis Rats. Pain Res Manag 2018,2018,1-8. (PMID: 10.1155/2018/519281430651902)
Kallenborn-Gerhardt W.; Lu R.; Bothe A.; Phosphodiesterase 2A localized in the spinal cord contributes to inflammatory pain processing. Anesthesiology 2014,121(2),372-382. (PMID: 10.1097/ALN.000000000000027024758774)
Bonetti M.; Fontana A.; Cotticelli B.; Volta G.D.; Guindani M.; Leonardi M.; Intraforaminal O(2)-O(3) versus periradicular steroidal infiltrations in lower back pain: Randomized controlled study. AJNR Am J Neuroradiol 2005,26(5),996-1000. (PMID: 15891150)
Melchionda D.; Milillo P.; Manente G.; Stoppino L.; Macarini L.; Treatment of radiculopathies: A study of efficacy and tollerability of paravertebral oxygen-ozone injections compared with pharmacological anti-inflammatory treatment. J Biol Regul Homeost Agents 2012,26(3),467-474. (PMID: 23034266)
Baillie G.S.; Tejeda G.S.; Kelly M.P.; Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: Inhibition and beyond. Nat Rev Drug Discov 2019,18(10),770-796. (PMID: 10.1038/s41573-019-0033-431388135)
Al-Tawashi A.; Gehring C.; Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability. Cell Commun Signal 2013,11(1),47. (PMID: 10.1186/1478-811X-11-4723826796)
Yan Y.; Zhao Y.; Lu Y.; Characterization of two novel phosphodiesterase 2 inhibitors Hcyb1 and PF-05180999 on depression- and anxiety-like behavior. Int J Neuropsychopharmacol 2023,26(6),415-425. (PMID: 10.1093/ijnp/pyad02037208298)
Wang L.; Xiaokaiti Y.; Wang G.; Inhibition of PDE2 reverses beta amyloid induced memory impairment through regulation of PKA/PKG-dependent neuro-inflammatory and apoptotic pathways. Sci Rep 2017,7(1),12044. (PMID: 10.1038/s41598-017-08070-228935920)
Seybold J.; Thomas D.; Witzenrath M.; Tumor necrosis factor-α–dependent expression of phosphodiesterase 2: Role in endothelial hyperpermeability. Blood 2005,105(9),3569-3576. (PMID: 10.1182/blood-2004-07-272915650061)
Xi M.; Sun T.; Chai S.; Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in Alzheimer’s disease. Eur J Med Chem 2022,232,114170. (PMID: 10.1016/j.ejmech.2022.11417035144038)
Helal C.J.; Arnold E.P.; Boyden T.L.; Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor. J Med Chem 2017,60(13),5673-5698. (PMID: 10.1021/acs.jmedchem.7b0039728574706)
Adapted and Recreated from “CREB Signalling Pathway”. 2022. Available From: https://app.biorender.com/biorender-templates.

R43 AG071045 United States AG NIA NIH HHS; R01 AG070873-01A1, 2021-2026 National Institute of Aging; R43 AG071045-01A1, 2021-2023 Small Business Innovation Research (SBIR) Program Phase I; 75N94019C00010 United States HD NICHD NIH HHS

Keywords: Phosphodiesterase 2 (PDE2 or PDE2A); cyclic AMP (cAMP); cyclic GMP (cGMP); neurodegenerative; neurodevelopmental disorders.; neuropsychiatric

E0399OZS9N (Cyclic AMP)
H2D2X058MU (Cyclic GMP)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2)
0 (Phosphodiesterase Inhibitors)
EC 3.1.4.17 (PDE2A protein, human)

Date Created: 20231019 Date Completed: 20240731 Latest Revision: 20240803

20240804

10.2174/1871527323666230811093126

37855295