Abstract
Background: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases.
Objective: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson’s, Huntington’s, and Alzheimer’s diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.
Keywords: Phosphodiesterase 10, PDE10 inhibition, CNS drug development, antipsychotics, schizophrenia, Parkinson’s disease, cognition.
Current Medicinal Chemistry
Title:Phosphodiesterase 10 Inhibitors - Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery
Volume: 25 Issue: 29
Author(s): Agnieszka Zagorska*, Anna Partyka, Adam Bucki, Alicja Gawalskax, Anna Czopek and Maciej Pawlowski
Affiliation:
- Department of Medicinal Chemistry, Jagiellonian University Medical College, Krakow,Poland
Keywords: Phosphodiesterase 10, PDE10 inhibition, CNS drug development, antipsychotics, schizophrenia, Parkinson’s disease, cognition.
Abstract: Background: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases.
Objective: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson’s, Huntington’s, and Alzheimer’s diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.
Export Options
About this article
Cite this article as:
Zagorska Agnieszka*, Partyka Anna, Bucki Adam, Gawalskax Alicja, Czopek Anna and Pawlowski Maciej, Phosphodiesterase 10 Inhibitors - Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery, Current Medicinal Chemistry 2018; 25 (29) . https://dx.doi.org/10.2174/0929867325666180309110629
DOI https://dx.doi.org/10.2174/0929867325666180309110629 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
Reversal in Cognition Impairments, Cholinergic Dysfunction, and Cerebral Oxidative Stress Through the Modulation of Ryanodine Receptors (RyRs) and Cysteinyl Leukotriene-1 (CysLT1) Receptors
Current Neurovascular Research Intramolecular Cyclization of Aryl Propargyl Ethers: A Straightforward and Convenient Approach to Benzofuran Derivatives
Current Organic Synthesis Selective Agents for Serotonin2C (5-HT2C) Receptor
Current Topics in Medicinal Chemistry Evaluation of the Effect of Nimodipine o.d. (Extended Release) vs Nimodipine t.i.d. in the Treatment of Peripheral Vertigo
Current Drug Delivery Design and Synthesis of Tetrahydroisoquinoline Derivatives as Anti-Angiogenesis and Anti-Cancer Agents
Anti-Cancer Agents in Medicinal Chemistry Exploring the Anti-Neuroinflammatory Potential of Steroid and Terpenoid-Derived Phytochemicals to Combat Alzheimer's Disease
Current Pharmaceutical Design A Computational View of COX-2 Inhibition
Anti-Cancer Agents in Medicinal Chemistry Biological Function and Medicinal Research Significance of G-Quadruplex Interactive Proteins
Current Topics in Medicinal Chemistry Paroxetine Use During Pregnancy and Perinatal Outcomes Including Types of Cardiac Malformations in Quebec and France: A Short Communication
Current Drug Safety Nanotechnology and Drug Delivery: Getting There is Only Half of the Challenge! (Commentary)
CNS & Neurological Disorders - Drug Targets From Treatment Adherence to Advanced Shared Decision Making: New Professional Strategies and Attitudes in Mental Health Care
Current Clinical Pharmacology The Chemical Biology of Immunophilin Ligands
Current Medicinal Chemistry Molecular Dynamics and Regulation of Butyrylcholinesterase Cholinergic Activity by RNA Binding Proteins
CNS & Neurological Disorders - Drug Targets Etanercept Improves Cognitive Performance and Increases eNOS and BDNF Expression During Experimental Vascular Dementia in Streptozotocin- induced Diabetes
Current Neurovascular Research Green and Facile Reaction of Gabapentin with Sulfonyl Chlorides to Synthesize Lactams and Sulfonamides Derivatives in Aqueous Medium
Letters in Organic Chemistry Genetic Analysis of CYP2D6 Polymorphism in Indian Populations and its Pharmacogenetic Implications
Current Pharmacogenomics and Personalized Medicine Is Androstadienone a Putative Human Pheromone?
Current Medicinal Chemistry Melatonin Therapy of Pediatric Sleep Disorders: Recent Advances, Why it Works, Who are the Candidates and How to Treat
Current Pediatric Reviews Biological Therapies For Inflammatory Bowel Disease: Research DrivesClinics
Mini-Reviews in Medicinal Chemistry Role of Presynaptic Glutamate Receptors in Pain Transmission at the Spinal Cord Level
Current Neuropharmacology