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| Project Title: | Phosphodiesterase-2 and mood disorders: target validation and drug discovery | |
| Principal Investigators (PI): |
O'DONNELL JAMES M
ZHAN |
|
| Project Number: | 1RC1MH088480-01 | |
| Organization: | WEST VIRGINIA UNIVERSITY | |
| Project Description: | ||
|---|---|---|
| [unreadable] (provided by applicant): The goal of this project is to validate phosphodiesterase-2 (PDE2) as a pharmacological target for the treatment of mood disorders and to discover novel, selective inhibitors. Inhibition of PDE2 enhances cGMP signaling by blocking its hydrolysis and produces anxiolytic and antidepressant effects on behavior. At present, there are few potent and selective PDE2 inhibitors. Our research has utilized high-level computational molecular modeling to predict structures for novel PDE2 inhibitors; some have been synthesized for neuropharmacological and behavioral evaluation. In order to advance drug discovery in this area, the following specific aims are proposed: 1) Design and synthesize PDE2 inhibitors and test for potency and selectivity in vitro; and 2) Determine the neurochemical and behavioral effects of PDE2 inhibitors and whether RNAi knockdown of PDE2 mimics the anxiolytic and antidepressant effects seen following pharmacological inhibition of PDE2. The completion of the proposed experiments will result in the identification of optimal molecular structures for PDE2 inhibition, synthesis of promising compounds, and verification of anxiolytic and antidepressant effects following both acute and chronic treatment. In addition, it will provide a non-pharmacological validation of PDE2 as a target relevant to mood disorders. This eventually will result in the development of novel drugs for the treatment of anxiety disorders and depression. In addition, the successful interactive molecular modeling/chemical synthesis/pharmacological characterization model will provide the basis for future drug discovery efforts involving other PDE families and other neuropsychopharmacological indications. Most PDE families are expressed in the brain and several appear to be of potential interest from a CNS drug discovery and development perspective. The rationale, strategy, approach, and analysis that are proposed for the present PDE2 project will provide a template for future drug discovery efforts involving other PDE families, especially since PDE inhibition has been shown to be a useful therapeutic approach (e.g., sildenafil; i.e., Viagra). [unreadable] PUBLIC HEALTH RELEVANCE: Mood disorder such as anxiety and depression are chronic debilitating diseases. Pharmacological treatments are not optimal due to poor effects in many individual patients, ineffectiveness for some conditions such as PTSD, and side effects that can cause lack of compliance. There is a need for drugs with novel mechanisms of action that may exhibit greater efficacy and fewer side effects. We have found that inhibitors of phosphodiesterase-2 (PDE2) have promise as anxiolytic and antidepressant drugs. The proposed research will discover, synthesize, and characterize the neurochemical and behavioral effects of novel PDE2 inhibitors. This may result in the identification of a new class of drugs for treating mood disorders. [unreadable] [unreadable] | ||
| Project Terms: | ||
| Abbott brand of sildenafil citrate Acute Address Adverse effects Affective Disorders Anti-Anxiety Agents Anti-Anxiety Drugs Antidepressant Agent Antidepressant Drugs Antidepressants Antidepressive Agents Antiphosphodiesterases Anxiety Anxiety Disorders Anxiolytic Agents Anxiolytics Area Arts Behavior Behavioral Brain Cell Communication and Signaling Cell Signaling Chronic Chronic depressive disorder Chronic depressive personality disorder Cyclic GMP Data Deoxyguanylate Cyclase Development Disease Disorder Drugs EC 1.14.13.39 EDRF Synthase Encephalon Encephalons Endogenous Nitrate Vasodilator Endothelium-Derived Growth Factor Synthase Endothelium-Derived Relaxing Factor Evaluation Exhibits Family Future GTP pyrophosphate-lyase (cyclizing) Goals Guanosine Cyclic 3',5'-Monophosphate Guanosine Cyclic Monophosphate Guanosine, cyclic 3',5'-(hydrogen phosphate) Guanyl Cyclase Guanylate Cyclase Guanylyl Cyclase-Activating Factor Synthase Hydrolysis In Vitro Individual Inosinate Cyclase Intracellular Communication and Signaling L-Arginine,NADPH[{..}]oxygen oxidoreductase (nitric-oxide-forming) Lead Lentiviral Vector Lentivirus Vector Macromolecular Structure Mammals, Mice Mediating Medication Methods and Techniques Methods, Other Mice Modeling Models, Molecular Molecular Models Molecular Structure Mononitrogen Monoxide Mood Disorders Murine Mus NADPH-Diaphorase NO Synthase NT mimic 2 Nerve Cells Nerve Unit Nervous System, Brain Neural Cell Neurochemistry Neurocyte Neurons Neuroses, Post-Traumatic Neuroses, Posttraumatic Nitric Oxide Nitric Oxide Synthase Nitric Oxide, Endothelium-Derived Nitric-Oxide Synthetase Nitrogen Monoxide Nitrogen Protoxide Nitrogen oxide Nucleic Acid Biochemistry, Molecular Modeling Outcome PDE PTSD Patients Pb element Peripheral Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Pharmacological Treatment Pharmacology-Psychopharmacology Phosphodiesterase Antagonists Phosphodiesterase Inhibitors Phosphodiesterases Phosphoric Diester Hydrolase Inhibitors Post-Transcriptional Gene Silencing Post-Transcriptional Gene Silencings Post-Traumatic Stress Disorders Posttranscriptional Gene Silencing Posttranscriptional Gene Silencings Pre-Clinical Model Preclinical Models Protein/Amino Acid Biochemistry, Molecular Modeling Psychopharmacology Psychopharmacology / Toxicology Quelling RNA Interference RNA Silencing RNA Silencings RNAi Research Science of neurochemistry Sequence-Specific Posttranscriptional Gene Silencing Signal Pathway Signal Transduction Signal Transduction Systems Signaling Stress Disorders, Post-Traumatic Stress Disorders, Posttraumatic Structure Techniques Testing Therapeutic Tranquilizing Agents, Minor Treatment Side Effects Validation Viagra analog antianxiety agent base biological signal transduction cGMP chemical synthesis chronic depression computational chemistry depression design designing disease/disorder drug discovery drug/agent endothelial cell derived relaxing factor experiment experimental research experimental study guanosine 3'5'monophosphate guanylyl cyclase heavy metal Pb heavy metal lead inhibitor inhibitor/antagonist interest mimic 2 molecular modeling mouse model neurochemistry neuronal neurotensin mimic 2 novel phosphoric diester hydrolase potency testing psychopharmacologic psychopharmacological public health relevance research study side effect sildenafil therapy adverse effect traumatic neurosis treatment adverse effect | ||
| Project Title: | Phosphodiesterase-2 and mood disorders: target validation and drug discovery | |
| Principal Investigators (PI): |
O'DONNELL JAMES M
ZHAN |
|
| Project Number: | 1RC1MH088480-01 | |
| Organization: | WEST VIRGINIA UNIVERSITY | |
| Project Categories: | ||
|---|---|---|
|
• Natural Sciences > Aging mechanisms by anatomy > Systems level > Hematologic system |
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| Other Information: | ||
| Fiscal Year: | 2009 | |
| Project Start Date: | 30 September 2009 | |
| Project End Date: | 31 August 2011 | Administering Institute Or Center: | MH |
| Project Funding Information: | ||
| Total Funding: | $483,316 | |
| Year | Funding Organization | Total Funding, $ |
|---|---|---|
| 2009 | NATIONAL INSTITUTE OF MENTAL HEALTH | $483,316 |
| Project Title: | Phosphodiesterase-2 and mood disorders: target validation and drug discovery | ||
| Principal Investigators (PI): |
O'DONNELL JAMES M
ZHAN |
||
| Project Number: | 1RC1MH088480-01 | ||
| Organization: | WEST VIRGINIA UNIVERSITY | ||
| Project_number | Title | Year | FY Total Cost |
|---|---|---|---|
| There are no results for this project in database. | |||
| Project Title: | Phosphodiesterase-2 and mood disorders: target validation and drug discovery | ||
| Principal Investigators (PI): |
O'DONNELL JAMES M
ZHAN |
||
| Project Number: | 1RC1MH088480-01 | ||
| Organization: | WEST VIRGINIA UNIVERSITY | ||
| Project number | Project title | Principal investigator | |
|---|---|---|---|
| There are no any related projects. | |||
| Project Title: | Phosphodiesterase-2 and mood disorders: target validation and drug discovery | |||
| Principal Investigators (PI): |
O'DONNELL JAMES M
ZHAN |
|||
| Project Number: | 1RC1MH088480-01 | |||
| Organization: | WEST VIRGINIA UNIVERSITY | |||
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