專題1 以磷酸二酯酶為靶標治療神經精神疾病、神經退行性疾病以及其他類型疾病

專題1 以磷酸二酯酶為靶標治療神經精神疾病、神經退行性疾病以及其他類型疾病

S1-1 Phosphodiesterase 1:a unique therapeutic target with multiple potential indications

Larry WENNOGLE

(Intra-Cellular Therapies,Inc.,New York,NY,USA)

S1-2 Targeting phosphodiesterases for cognition enhancement: a translational approach

Jos PRICKAERTS

(Department of Psychiatry and Neuropsychology,School for Mental Health and Neuroscience,Maas?tricht University,Maastricht,The Netherlands)

Dr.Jos PRICKAEERRTTSS is associate professor of Experimental Neuropsychopharmacology at the Department of Psychiatry and Neuropsychology at Maastricht University(The Netherlands). He studied biology at Utrecht University and obtained his PhD degree on′Memory Formation, Neurodegeneration and Drugs′at the Department of Psychiatry and Neuropsychology at Maas?tricht University(1998).Thereafter,he was working as a researcher in multidisciplinary teams at Maastricht University and eventually pharmaceutical industry(Johnson and Johnson PRD, Belgium).Ten years ago,he returned to the Department of Psychiatry and Neuropsychology at Maastricht University and his research focuses on signal transduction and plasticity.In particular, the role of phosphodiesterases(PDEs)and growth factors in this respect is being studied.His major aim is to unravel the mechanism of action of signaling pathways both in health and disease (mainly Alzheimer disease),while at the same time exploring the therapeutic potential of key players in the affected signaling pathways.He was the first to demonstrate the cognition enhancing potential of PDE5 inhibition and he is a leading expert in the field of PDEs and invited for numerous symposia,writing book chapters,discussions in forums/meetings, as well as consultant for pharmaceutical companies.With the latter there is also a substantial collaboration to develop and test new cognition enhancers.He has co-authored over 160 scientific papers(H-index 47),contributed to 9 book chapters and has 4 patents.Study grants have been obtained from pharmaceutical industry,Dutch Government(eg The Netherlands Organization for Health Research and Development)and the Alzheimer Foundation Netherlands.His research involves working with animals and human subjects in a translational context with the Faculty of Psychology and Neuro?science(adults)and the memory clinic(elderly,patients with Alzheimer disease).

Abstract:Cyclic adenosine monophosphate(cAMP)and/or cyclic guanosine monophosphate(cGMP) have been suggested to play specific roles in processes of memory.These cyclic nucleotides are hydrolyzed by specific enzymes,iephosphodiesterases(PDEs).Thus,selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory.Studies with different timing of treatment with specific PDE inhibitors indicated that distinct underlying signaling pathways for early and late consolidation processes exist corresponding to specific time-windows for memory consolidation into longterm memory.There is evidence that the underlying mechanisms of PDE inhibition on the observed behavioral effects are independent of possible cerebrovascular effects.Most likely the underlying mech?anisms are a cGMP/PKG pathway for early consolidation processes and a cAMP/PKA pathway for late consolidation processes.In addition,the early-phase cGMP/PKG signaling actually requires late-phase cAMP/PKA-signaling in long-term memory formation.Recently,the effects of specific PDE inhibitors are explored on other cognitive domains including acquisition processes/short-term memory and infor?mation processing.It will be shown that elevation of central cGMP levels or cAMP levels after treatment with a specific PDE inhibitor both improve acquisition processes/short-term memory.In vitrostudying the effects of PDE inhibitors on long-term potentiation,the physiological substrate of memory,supportthein vivodata and further show that AMPA receptor trafficking very likely mediates the memory enhancing effects.In a translational approach we initially also investigated the effects of cGMP elevation via PDE5 inhibition with vardenafil or sildenafil on cognition in humans.However,in contrast to studies with rodents and monkeys,PDE5 inhibition had no effect in humans on cognition including memory processes.It is clear that the transition of a drug from preclinical to clinical creates translational hurdles.Nevertheless,based on the expression patterns of its isoforms in the brain,PDE4,which is cAMP specific,appears more interesting for CNS targeting than PDE5.Indeed we found that a low dose of the PDE inhibitor roflumilast clearly improved cognition in humans.Interestingly,this pro-cognitive effect was not associated with emetic side effects(nausea,vomiting),which are commonly associated with PDE4 inhibition.Based on our data we suggest that the future for disease-specific PDE4 enzyme inhibition lies in the development of PDE4 isoform-specific inhibitors without emetic effects.Within the context as described above,the latest results of specific PDE inhibitors on cognitive processes will be presented and its implications will be discussed for finding and testing new cognition enhancers.

Key words:phosphodiesterases;cognition;memory

S1-3 Phosphodiesterases:novel targets for treatment of alcoholism

LIU Xin1＊,WEN Rui-ting2,3＊,GONG Mei-fang4＊,XU Ying5＊,Nicolas GRAHAME6,XU Jiang-ping5, LIANG Jian-hui3,Marco CONTI7,ZHANG Han-ting1,2

(1.Institute of Pharmacology,Taishan Medical University,Tai′an 271016,China;2.Departments of Behavioral Medicine&Psychiatry and Physiology&Pharmacology,Blanchette Rockefeller Neurosciences Institute,West Virginia University Health Sciences Center,Morgantown,WV 26506,USA;3.Department of Molecular and Cellular Pharmacology,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China;4.Department of Pharmacology,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China;5.Department of Pharmaceutical Sciences,State University of New York at Buffalo,Buffalo,NY 14214,USA;6.Department of Psychology,Indiana University-Purdue University Indianapolis,Indianapolis,IN,46202,USA;7.Center for Reproductive Sciences,Department of Obstetrics,Gynecology and Reproductive Sciences,University of California,San Francisco,CA 94143,USA)

張漢霆，博士，泰山學者海外特聘專家，泰山醫學院藥理學研究所所長、藥學院教授，美國西弗吉尼亞大學醫學院教授及博導，中國旅美科技協會西弗吉尼亞分會會長，美國西弗吉尼亞華人協會會長。張博士1987年7月畢業于廣州南方醫科大學(原第一軍醫大學)醫療系，并獲得醫學學士學位；1992和1995年在軍事醫學科學院毒物藥物研究所師從羅質璞教授和秦伯益院士,分別獲得藥理學碩士及博士學位。1998年赴美留學，先后在美國路易斯安那州立大學和田納西大學衛生科學中心，從事神經精神藥理學博士后研究；2005年起于美國西弗吉尼亞大學醫學院行為醫學與精神疾病系任助教授，博士生導師及終身教授。2015年起受聘為山東省政府“泰山學者海外特聘專家”，泰山醫學院藥理研究所所長。張博士一直從事磷酸二酯酶(PDE)的生物功能與機制研究。在PDE對中樞功能的調控方面取得了國際同行公認的成就。他在國際上第一個證明腦內PDE4D對抑郁以及PDE4對飲酒的重要調節作用，并闡明腦內PDE4亞型（PDE4A,PDE4B,PDE4D）對抑郁、焦慮和認知等行為的不同調控及機制。張博士先后兩次（2006，2008）獲得美國NARSAD青年科學家獎（NARSAD Young Investigator Award）；并多次擔任重要國際會議的主席和（或）作大會報告。應邀在中、美、歐等地的高校及科研院所做學術報告100余場。在Journal of Neuroscience，Neuropsychopharmacology，Trends in Pharmacological Sciences等高影響力雜志上發表論文及綜述80余篇，書稿（篇章）18部。論文他引次數2600余次；H指數為28。作為國際著名的磷酸二酯酶研究專家，主編英文版磷酸二酯酶專著1部（Phosphodiesterases:CNS Functions and Diseases，Springer出版社），參與編寫磷酸二酯酶專著五部（均為英文版）張博士還擔任海內外多種科研基金/項目的評審專家，包括美國國立衛生研究院(NIH)研究基金，美國弗羅里達州衛生廳老年性癡呆研究專項基金，歐洲Alzheimer病研究基金ISAO，荷蘭轉化研究項目（ZonMw′s PTO），中國國家自然科學基金重點項目和重大國際合作項目，教育部“長江學者特聘教授/講座教授”計劃，教育部自費留學獎學金（中國駐美使館轄區），等。此外，張博士還擔任14種國際學術期刊的主編、副主編或編委，包括Current Pharmaceutical Design客座主編，Frontiers in Pharmacology副主編，Frontiers in Aging Neuroscience副主編，Metabolic Brain Disease常務副主編,Scientific Reports和Journal of Clinical Pharmacology等雜志的常務編委。同時擔任包括PNAS，Journal of Neuroscience,Neuropsychopharma?cology等在內的50余種國際期刊的審稿人。此外，張博士作為旅美華人杰出代表于2011年胡錦濤主席訪美和2012，2015年習近平主席訪美期間，先后受到兩位領導人的親切接見。

Abstract:OBJECTIVEAlcoholism is one of the most damaging psychiatric disorders and causes serious social and health problems in the world.However,there are no ideal treatments for this disease in clinic. Phosphodiesterases(PDEs)are a superfamily of enzymes consisting of 11 PDE families that hydrolyze cyclic AMP(cAMP)and/or cyclic GMP(cGMP).Among them,PDE4 is critical in the control of intracellular cAMP levels and has been shown to play an important role in the regulation of ethanol consumption. However,the functional role of PDE4 in mediating alcoholism remains unclear.METHODSEthanol drinking and preference were examined using the two-bottle choice and/or drinking-in-dark(DID)test in high alcohol preferring(HAP)animals,including C57,HAP,and PDE4-subtype knockout mice,and Fawn-Hooded(FH/Wjd)rats,treated with or without the PDE4 inhibitor rolipram or roflumilast.Ethanol withdrawal-induced anxiety-and depressive-like behaviors were examined using the elevated plusmaze,holeboard,forced-swim,and tail-suspension tests in C57 mice or FH rats in the presence of PDE4 inhibition.Levels of cAMP,CREB were determined in brain regions.RESULTSTreatment with rolipram or roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in C57 and HAP mice as well as FH rats.Mice deficient in PDE4B,but not PDE4D,displayed similar effects to general PDE4 inhibition.In addition,rolipram reversed ethanol withdrawal-induced anxietyand depressive-like behaviors 1 d and 14 d,respectively,following withdrawal from ethanol drinking in the two-bottle choice in C57 mice or FH rats.Locomotor activity was not changed in either mice or rats treated with the PDE4 inhibitors.Levels of cAMP,pCREB in the brain were increased by rolipram.CONCLUSIONThe results provide solid evidence for the important role of PDE4 in ethanol consump?tionand ethanol withdrawal-induced symptoms.Inhibitors of PDE4,in particular the PDE4B isoform, can be a novel class of treatment for alcoholism.

Key words:phosphodiesterase;alcohol drinking;alcoholism;anxiety,depression;rodents

＊Co-first author.

S1-4 PDE10A inhibitor in addiction

MU Ying,ZHEN Xue-chu

(Jiangsu Key Laboratory of translational research for Neuro-psychiatric diseases,College of Pharmaceutical Sciences,Soochow University,Suzhou,China)

Dr.ZHEN XueN Xue-chuchu is a professor of neuropsychopharmacology in Department of Pharma?cology,Soochow University College of Pharmaceutical Sciences,Suzhou,China.He was formally a professor and principle investigator in Shanghai Institute of MaterialMedica,Chinese Academy of Sciences between 2006-2011.In 2003-2006,he became associate professor in department of Pharmacology and physiology at City University of New York Medical School.He received his PhD in University of Geneva,Switzerland in 1996.His lab is focused on neuro?transmission and diseases and CNS drug discovery targeted to schizophrenia,Parkinson disease and drug abuse.He has published more than 120 research papers and review articles in peered-reviewed international journals.He is awarded national outstanding young scientist in 2008.His research is supported by National Science Foundation of China,Ministry of Science and Technology of China.

Abstract:Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system.These phenomena are usually referred as′drug-induced neuro?plasticity′and depend on changes in gene expression.The cAMP response element binding protein (CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse.Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine.Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine.The results show that MP-10 2.5 mg·kg-1, administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP.More?over,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP.Additionally,chronic treatment with MP-10 2.5 mg·kg-1decreased expression of phosphorylated CREB(pCREB)in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex (ACC)as well as decreased expression of ΔFosB in the shell of NAc and ACC.These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction.Since the MP-10 has rela?tive short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure.The new compound exhibited promising potential in schizo?phrenia and addiction treatment.

Corresponding author:ZHEN Xue-chu,E-mail:zhenxuechu@suda.edu.cn

S1-5 Regulation and function of cyclic nucleotide phosphodiesterases in pathological vascular remodeling

YAN Chen

(Aab Cardiovascular Research Institute,University of Rochester,Rochester,New York,USA)

Dr.YAN Chen Chen received her Bachelor and Master degrees in the field of Biochemistry and Genetics,respectively,from Fudan University,Shanghai,China.She completed her PhD.in Pharmacology at University of Washington in Seattle,USA.Currently,she is a tenured professor in the Cardiovascular Research Institute,University of Rochester School of Medicine and Dentistry,Rochester,USA.Dr.YAN has established a well-recognized and well-funded research program in the area of cyclic nucleotide signaling and cardiovascular biology by focusing on a family of enzymes called phosphodiesterases(PDE)that degrade cyclic nucleotides (cAMP and cGMP).The ongoing studies in Dr.YAN′s lab usingin vitroandin vivoapproaches have been focused on elucidating the roles and underlying mechanisms of PDE activation or inhibition in various cardiovascular diseases.To date,she has more than 130 SCI publications in a number of prestigious journals such asPNAS,CirculationandCirculation Research,etc.She serves on the editorial board of several journals such asArterioscletosis,Thrombosis,andVascular Biology(ATVB)andJournal of Molecular and Cellular Cardiology(JMCC),as well as serves as an ad hoc reviewer for many other cardiovascular-related journals.She was a recipient of American Heart Association Established Investigator Award.

Abstract:Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,heart,lung,and peripheral vasculatures.Pathological vascular remodeling occurs in response to a variety of vascular insults such as mechanical(angioplasty or stenting)or biological (lipids,diabetes,smoking,or virus)injuries.It is a polygenic process involving multiple cell types in the vessel wall or circulation,including endothelial cells(ECs),smooth muscle cells(SMCs),fibroblasts, leukocytes,and platelets.One of hallmarks is the transition of vascular smooth muscle cells(SMCs)from a differentiated/quiescent contractile phenotype to a myofibroblast-like dedifferentiated/active so-called synthetic phenotype.Synthetic SMCs are proliferatory,migratory,secretory and inflammatory, playing key roles in the pathogenesis of vascular remodeling.In the normal vessel,ECs synthesize and secrete biological substances such as prostacyclins(PGI2)and nitric oxide(NO)that not only function as vasodilators but also inhibit SMC phenotype transition and other properties associated with the synthetic phenotype.Cyclic nucleotides cAMP and cGMP are primary mediators of PGI2and NO, respectively,and play critical roles in control vascular structural integrity and function.Cyclic nucleo?tides are controlled by selective activation or inhibition of distinct cyclic nucleotide phosphodiesterase (PDE)isozymes catalyzing the degradation reaction.To date,more than 60 different PDE isoenzymes derived from 22 genes are identified and grouped into 11 broad families(PDE1-PDE11).PDEs are expressed in a cell/tissue-specific manner and only a few enzymes are expressed in any single cell type.Through systematic assessment of the expression levels of all known PDE isoforms in contractile versus synthetic SMCs,we found that the expression levels of a number of PDE are significantly altered between two SMC phenotypes.We then explored the functional roles and underlying mecha?nisms of these altered PDEs in vascular SMCs pathogenesis and vascular remodelingin vitroandin vivousing a variety of gain-of-or loss-of-function approaches.For example,we found that Ca2+/calmodulinstimulated cAMP/cGMP-hydrolyzing PDE1C is selectively expressed in synthetic SMCsin vitroand in various vascular disease modelsin vivo.PDE1C upregulation contributes to a number of pathogenic functions of synthetic SMCs,such as cell proliferation,migration,and matrix protein metabolism. PDE1C deficiency markedly attenuates intimal hyperplasia,atherosclerosis,and aortic aneurysm in experimental mouse disease models.These findings suggest that PDE1C functions as a key regulator of the synthetic SMC pathology in vascular remodeling.Inhibiting PDE1C function may represent a novel therapeutic strategy for protecting against the pathogenesis of vascular diseases.

Key words:phosphodiesterases;smooth muscle cells;vascular remodeling

S1-6 Role of PDE4D splice variants in the mediation of antidepressant and cognition-enhancing actions and its mechanisms

JIN Zeng-liang1,2,WANG Zhen-zhen3,XU Yuan-yuan1,YANG Wei-xing1,LI Yun-feng1

（1.Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Beijing 100850,China;2.Department of Pharmacology,Capital Medical University,Beijing,China；3.Department of Pharmacology,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China）

Abstract:OBJECTIVEPhosphodiesterase 4(PDE4),specific for cyclic AMP(cAMP)-hydrolyzing,has four isoforms(PDE4A-D)with at least 25 splice variants.PDE4 inhibitors produce definite antidepres?sant-like and cognitive-enhancing effects.However,none of PDE4 inhibitors has yet been approved for clinical utility so far due to the concomitant side effects.The present research is to explore the splice variants of PDE4D responsible for antidepressant-like and cognitive-enhancing effects of PDE4 inhibitors but not side effects.METHODSLong-form PDE4Ds were silenced by the bilateral microinfusion of lentiviral vector containing miRNAs(4DmiR)into the prefrontal cortex(PFC),PDE4D4 or D5 was over?expressed by the bilateral microinfusion of lentiviral vector containing full cDNA into hippocampus.Anti?depressant-like behaviors were measured by tail-suspension test(TST),forced swimming test(FST)and chronic unpredictable stress model.Cognitive behaviors were measured by the novel object recog?nition test(NOR)and Morris water maze test(MWM)in both normal mice and the mice with chronic unpredictable stress-induced memory deficits.The emetic potential was evaluated by the assessment of the anaesthetic reversal effect,a surrogate of the emesis test in non-vomiting species.The expres?sions of PDE4 isoforms/splice variants and cAMP level were examined by Western-blot and ELISA analysis.The dendritic complexity and spine density were assessed by Golgi staining.RESULTS(1) High and specific expression of EGFP(green,indicator of 4DmiR expression)in PFC was observed under fluorescence microscopy.(2)4DmiR significantly down-regulated PDE4D4/5 splice variants,but not PDE4A,PDE4B or PDE4D1/2/3.(3)4DmiR treatments significantly increased cAMP signaling and dendritic complexity in PFC.(4)Rolipram and/or 4DmiR treatments significantly decreased immobility in TST and FST.(5)Rolipram and/or 4DmiR treatments reversed the depressive-like behaviors in chronically stressed mice,including the reduced sucrose preference,prolonged latency to novelty-sup?pressed feeding and increased immobility in FST.(6)Rolipram and/or 4DmiR treatments significantly increased the recognition index in NOR task and both the entries and durations in MWM task.(7)Rolip?ram and/or 4DmiR treatments reversed the memory deficits in chronically stressed mice,including the reduced the recognition index in NOR task and the decreased durations in MWM task.(8)Rolipram and/or 4DmiR treatments reversed the decreased cAMP signaling,dendritic complexity and spine density. (9)Rolipram or plus 4DmiR treatment significantly decreased the duration of anaesthesia in the alpha2 adrenergic receptor-mediated anesthesia,but not 4DmiR treatment alone.（10）Hippocampal overexpression of PDE4D5,but not PDE4D4,produced depressive-like and cognitive defect behaviors, which were reversed by rolipram.The measurements including cAMP signaling,dendritic complexity andin vivohippocampal LTP,showed the same changes.CONCLUSIONLong-form PDE4Ds,espe?cially the PDE4D5,are the major isoforms responsible for antidepressant-like and cognitive-enhancing effects with little side effects.The critical roles of long-form PDE4Ds are mediated by their regulation of cAMP signaling pathway and neuroplasticity.

Key words:phosphodiesterase 4D;RNA interference;overexpressions;antidepressant;cognitive; prefrontal cortex;hippocampus

WENNOOGGLLEE received his PhD in biochemistry and molecular biology under Howard Berg and Marvin Caruthers at the University of Colorado,in Boulder,Colorado,USA.He stayed there to complete post-doctoral studies covering the red blood cell membrane structurefunctional relationships.His second post-doctoral fellowship was at the Pasteur Institute in Paris France where he studied structure-function relations of the nicotinic acetylcholine receptor under Jean-Pierre Changeux.During his professional career,including 37 years working in the phar?maceutical industry,Dr.WENNOGLE has focused on discovering and developing novel agents as therapies for human diseases.He played a significant role in the identification of nine drug candidates that were evaluated in human clinical trials,including efforts in cardiovas? cular diseases(hypertension,reperfusion injury),inflammation,diabetes,and disorders of the central nervous system. Two drugs were approved for human use:Prexige(COX2 inhibitor for arthritis)and benazepril(ACE inhibitor for hypertension) during his tenure of 20 years at CIBA-Geigy/Novartis,in part due to his efforts.His group identified the atrial narriuretic peptide degrading enzyme now called Neprilysin.Novartis recently won approval of a novel Neprilysin inhibitor-angiotensinⅡreceptor antagonist combination LCZ696 for heart failure(Entresto?).For the past fifteen years,he has headed a Drug Discovery effort at Intra-Cellular Therapies(ITI-NASDAQ ITCI).ITI is dedicated to developing drugs for major unmet medical needs and currently has two drug candidates in human clinical trials including Lumateperone(ITI-007)for schizo?phrenia and ITI-214,a phosphodiesterase I inhibitor,for cognitive dysfunction in schizophrenia and other indications including heart failure.To enable these efforts,Dr.WENNOGLE assembled a talented team of drug discovery scientists including veteran medicinal chemists and pharmacologist and put in place a highly efficient platform of discovery capabilities employing state-of-the-art methods.They have assembled methods to maximize or minimize brain penetration and oral bio-availability of drug candidates.Dr.WENNOGLE identified the licensing opportunity for the ITI-007 portfolio.His group discovered the clinical candidate compound ITI-007 and managed all studies leading to the IND submission.Their Drug Discovery Group is the leader in the phosphodiesteraseⅠinhibitor field and they discovered and developed the potent and selective PDE1 inhibitor ITI-214.ITI-214 has completed four phase one human clinical trials and will soon enter phase two human testing. Earlier in his career,Dr.WENNOGLE discovered novel methods of efficiently screening and optimization drug candidate using combinatorial chemical libraries.For the past 15 years,he has been collaborating with a team of Alzheimer disease experts,including Nobel Laureate Paul GREENGARD of Rockefeller University,to identify and exploit novel targets with the goal to discover new therapeutics for Alzheimer disease.He has a major focus on therapeutics for degenerative disorders,including heart failure and ocular diseases.They have been exploring novel treatments for such diseases.Dr.WENNOGLE is a Fellow of the New York Academy of Sciences and currently holds an Adjunct Professorship at Rutgers University,the State University of New Jersey.

Cyclic-nucleotide phosphodiesterase 1(PDE1)is a unique enzyme family hydrolyzing both cyclic guanosine monophosphate(cGMP)and cyclic adenosine monophosphate(cAMP)intra-cellular signaling molecules.A unique aspect of this enzyme family is its activation by calcium-calmodulin upon excitation of excitatory cells such as neurons and cardiomyocytes.In chronic degenerative diseases such as Parkinson disease,Alzheimer disease and heart failure,over-stimulation and chronic excessive levels of intra-cellular calcium leads to cell death.Targeting the PDE1 enzyme family with enzyme inhibitors is a novel approach to develop therapeutic agents for degenerative disorders.ITI-214 is a potent,and selective PDE1 inhibitor that has been tested in four human clinical trials.It is safe and well tolerated even at high dose levels that lead to high plasma and cerebral spinal fluid levels.In animal models,ITI-214 has cognitive enhancing properties as demonstrated in the rat novel object recognition model.Using a unilateral 6-hydroxy-dopamine lesion mouse model,the cylinder test readout of front paw use indicated that ITI-214 displays L-DOPA sparing effects ITI-214 reverses catalepsyinduced by the potent dopamine D2 receptor antagonist haloperidol,indicating potential applications in Parkinson disease and as an adjunctive treatment in schizophrenia.Aspects of the Intra-Cellular Therapies PDE1 inhibitor program will be outlined and the potential application to multiple therapeutic areas will be discussed.

cyclic-nucleotide phosphodiesterase 1;calmodulin-activation;cognition;degenerative;therapies

ZHANG Han-ting,E-mail:hzhang@hsc.wvu.edu