Abstract
Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant- like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold- based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.
Keywords: Phosphodiesterase-4 (PDE4), antidepressant, cAMP signaling, splice variant, brain distribution, RNA interference (RNAi)
Current Pharmaceutical Design
Title: Cyclic AMP-Specific Phosphodiesterase-4 as a Target for the Development of Antidepressant Drugs
Volume: 15 Issue: 14
Author(s): Han-Ting Zhang
Affiliation:
Keywords: Phosphodiesterase-4 (PDE4), antidepressant, cAMP signaling, splice variant, brain distribution, RNA interference (RNAi)
Abstract: Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant- like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold- based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.
Export Options
About this article
Cite this article as:
Zhang Han-Ting, Cyclic AMP-Specific Phosphodiesterase-4 as a Target for the Development of Antidepressant Drugs, Current Pharmaceutical Design 2009; 15 (14) . https://dx.doi.org/10.2174/138161209788168092
DOI https://dx.doi.org/10.2174/138161209788168092 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Role of Extracellular Adenosine in Chemical Neurotransmission in the Hippocampus and Basal Ganglia: Pharmacological and Clinical Aspects
Current Topics in Medicinal Chemistry Neural Stem Cells Transplanted in a Mouse Model of Parkinson’s Disease Differentiate to Neuronal Phenotypes and Reduce Rotational Deficit
CNS & Neurological Disorders - Drug Targets Polyamine Modulation of NMDARs as a Mechanism to Reduce Effects of Alcohol Dependence
Recent Patents on CNS Drug Discovery (Discontinued) Organometallic Complexes: New Tools for Chemotherapy
Current Medicinal Chemistry Gene Therapy for Parkinsons and Alzheimers Diseases: from the Bench to Clinical Trials
Current Pharmaceutical Design Inflammatory Process in Parkinsons Disease: Role for Cytokines
Current Pharmaceutical Design Omega-3 Fatty Acids Supplementation in Psychiatric Disorders: A Systematic Review
Current Psychopharmacology Women and Schizophrenia: Sex-Based Pharmacotherapy
Current Psychiatry Reviews Antipsychotics and Cognitive Functioning: A Critical Review
Current Psychopharmacology The Role of Oxidative Stress in Huntington’s Disease: Are Antioxidants Good Therapeutic Candidates?
Current Drug Targets Suicide Prevention in Schizophrenia: Do Long-Acting Injectable Antipsychotics (LAIs) have a Role?
CNS & Neurological Disorders - Drug Targets Prevalence of Pre-Existing Risk Factors for Adverse Events Associated with Atypical Antipsychotics Among Commercially Insured and Medicaid Insured Patients Newly Initiating Atypical Antipsychotics
Current Drug Safety Neural Basis of Dental Pulp Stem Cells and its Potential Application in Parkinson’s Disease
CNS & Neurological Disorders - Drug Targets Current Therapeutic Options for Alzheimers Disease
Current Genomics Possible Targets of Herbals for Type 3 Diabetes: A Review
Current Traditional Medicine Antipsychotic Augmentation Strategies to Ameliorate Negative and Cognitive Symptoms in Schizophrenia; Implications for Future Research
Central Nervous System Agents in Medicinal Chemistry Tau as a Therapeutic Target for Alzheimers Disease
Current Alzheimer Research Pharmacotherapy of Schizophrenia: The Past, Present and Future
Current Drug Therapy Neuroregeneration in Parkinson’s Disease: From Proteins to Small Molecules
Current Neuropharmacology Antidepressants: Update on Benefits and Risks
Current Psychopharmacology