Abstract
Clinically utilized antipsychotic agents share as a common mechanism the ability to antagonize dopamine D2 receptors and it is widely assumed that this activity contributes to their efficacy against the positive symptoms of schizophrenia. The efficacy of currently marketed antipsychotic agents on the negative and cognitive symptoms of this disease, however, is not optimal. One alternate hypothesis to the “dopamine hypothesis” of schizophrenia derives from the observation that antagonists of NMDA receptor activity better mimic the symptomatology of schizophrenia in its entirety than do dopamine agonists. Findings from this line of research have led to the NMDA receptor hypofunction (or glutamate dysfunction) hypothesis of schizophrenia, which complements existing research implicating dopamine dysfunction in the disease. According to the NMDA receptor hypofunction hypothesis, any treatment that enhances NMDA receptor activity may prove useful for the treatment of the complex symptoms that define schizophrenia. This idea is now supported by numerous clinical studies that have reported an efficacious response following treatment with activators of the NMDA receptor co-agonist glycineB site. One area of study, aimed at potentiating the NMDA receptor via activation of the glycineB site is small molecule blockade of the glycine reuptake transporter type 1 (GlyT1). Broadly, these efforts have focused on derivatives of the substrate inhibitor, sarcosine, and non-sarcosine based GlyT1 inhibitors. Accordingly, the following review discusses the development of both sarcosine and non-sarcosine based GlyT1 inhibitors and their current status as putative treatments for schizophrenia and other disorders associated with NMDA receptor hypoactivity
Keywords: NMDA receptor, fluoxetine, Non-sarcosine-Derived GlyT1 Inhibitors, GLYT1 mouse models, rat hippocampal slices
Current Topics in Medicinal Chemistry
Title: Progress in the Preparation and Testing of Glycine Transporter Type-1 (GlyT1) Inhibitors
Volume: 6 Issue: 17
Author(s): Craig W. Lindsley, Scott E. Wolkenberg and Gene G. Kinney
Affiliation:
Keywords: NMDA receptor, fluoxetine, Non-sarcosine-Derived GlyT1 Inhibitors, GLYT1 mouse models, rat hippocampal slices
Abstract: Clinically utilized antipsychotic agents share as a common mechanism the ability to antagonize dopamine D2 receptors and it is widely assumed that this activity contributes to their efficacy against the positive symptoms of schizophrenia. The efficacy of currently marketed antipsychotic agents on the negative and cognitive symptoms of this disease, however, is not optimal. One alternate hypothesis to the “dopamine hypothesis” of schizophrenia derives from the observation that antagonists of NMDA receptor activity better mimic the symptomatology of schizophrenia in its entirety than do dopamine agonists. Findings from this line of research have led to the NMDA receptor hypofunction (or glutamate dysfunction) hypothesis of schizophrenia, which complements existing research implicating dopamine dysfunction in the disease. According to the NMDA receptor hypofunction hypothesis, any treatment that enhances NMDA receptor activity may prove useful for the treatment of the complex symptoms that define schizophrenia. This idea is now supported by numerous clinical studies that have reported an efficacious response following treatment with activators of the NMDA receptor co-agonist glycineB site. One area of study, aimed at potentiating the NMDA receptor via activation of the glycineB site is small molecule blockade of the glycine reuptake transporter type 1 (GlyT1). Broadly, these efforts have focused on derivatives of the substrate inhibitor, sarcosine, and non-sarcosine based GlyT1 inhibitors. Accordingly, the following review discusses the development of both sarcosine and non-sarcosine based GlyT1 inhibitors and their current status as putative treatments for schizophrenia and other disorders associated with NMDA receptor hypoactivity
Export Options
About this article
Cite this article as:
Lindsley W. Craig, Wolkenberg E. Scott and Kinney G. Gene, Progress in the Preparation and Testing of Glycine Transporter Type-1 (GlyT1) Inhibitors, Current Topics in Medicinal Chemistry 2006; 6 (17) . https://dx.doi.org/10.2174/156802606778249784
DOI https://dx.doi.org/10.2174/156802606778249784 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Adaptogens—History and Future Perspectives
Adaptogens are pharmacologically active compounds or plant extracts that are associated with the ability to enhance the body’s stability against stress. The intake of adaptogens is associated not only with a better ability to adapt to stress and maintain or normalise metabolic functions but also with better mental and physical ...read more
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
![](/images/wayfinder.jpg)
- 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
-
Anti-Inflammatory Therapy for Alzheimer’s Disease from Epidemiological Fact to New Mechanisms of Action
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Ganglioside Mimicry as a Cause of Guillain-Barre Syndrome
CNS & Neurological Disorders - Drug Targets Recreational Drug Misuse and Stroke
Current Drug Abuse Reviews Exercise Training-Associated Changes in Arterial Stiffness and Endothelium-Derived Vasoactive Factors
Current Hypertension Reviews New Patents on Topical Anesthetics
Recent Patents on Inflammation & Allergy Drug Discovery Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents
Current Medicinal Chemistry Management of Blood Pressure and Heart Rate in Patients with Acute Stroke
Current Pharmaceutical Design An Overview of Parkinsons Disease and the Cannabinoid System and Possible Benefits of Cannabinoid-Based Treatments
Current Medicinal Chemistry Stem Cell Therapy: A Promising Approach in Treatment of COVID-19
Current Stem Cell Research & Therapy Pharmacologic Treatment of Rapid Ejaculation: Levels of Evidence-Based Review
Current Clinical Pharmacology Alzheimer’s Disease-like Early-phase Brain Pathogenesis: Self-curing Amelioration of Neurodegeneration from Pro-inflammatory ‘Wounding’ to Anti-inflammatory ‘Healing’
Current Alzheimer Research Inflammation-Mediating Proteases: Structure, Function in (Patho) Physiology and Inhibition
Protein & Peptide Letters Molecular Pharmacology of Non-L-type Calcium Channels
Current Pharmaceutical Design Phosphodiesterases as Therapeutic Targets for Huntington’s Disease
Current Pharmaceutical Design The Role of HTS in Drug Discovery at the University of Michigan
Combinatorial Chemistry & High Throughput Screening Mitochondria: A Connecting Link in the Major Depressive Disorder Jigsaw
Current Neuropharmacology Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight
Current Neuropharmacology Emerging Signalling and Protein Interactions Mediated Via Metabotropic Glutamate Receptors
Current Drug Targets - CNS & Neurological Disorders Erythropoietin: New Approaches to Improved Molecular Designs and Therapeutic Alternatives
Current Pharmaceutical Design Pathophysiology of Blood-Spinal Cord Barrier in Traumatic Injury and Repair
Current Pharmaceutical Design