Abstract
For more than four decades there has been a search for selective inhibitors of GABA transporters. This has led to potent and selective inhibitors of the cloned GABA transporter subtype GAT1, which is responsible for a majority of neuronal GABA transport. The only clinically approved compound with this mechanism of action is Tiagabine. Other GABA transporter subtypes have not been targeted with comparable selectivity and potency. We here review a comprehensive series of competitive inhibitors that provide information about the GABA recognition site and summarise the structure-activity relations in a ligand-based pharmacophore model that suggests how future compounds could be designed. Finally, some of the recent results on subtype-characterised competitive inhibitors and recent lipophilic aromatic GABA uptake inhibitors are reviewed.
Keywords: Acyclic GABA Analogues, THPO, Nipecotic Acid, Aminocyclohexanecarboxylic Acid (ACHC), GABA uptake assay
Current Topics in Medicinal Chemistry
Title: Structure-Activity Relationships of Selective GABA Uptake Inhibitors
Volume: 6 Issue: 17
Author(s): Signe Hog, Jeremy R. Greenwood, Karsten B. Madsen, Orla M. Larsson, Bente Frolund, Arne Schousboe, Povl Krogsgaard-Larsen and Rasmus P. Clausen
Affiliation:
Keywords: Acyclic GABA Analogues, THPO, Nipecotic Acid, Aminocyclohexanecarboxylic Acid (ACHC), GABA uptake assay
Abstract: For more than four decades there has been a search for selective inhibitors of GABA transporters. This has led to potent and selective inhibitors of the cloned GABA transporter subtype GAT1, which is responsible for a majority of neuronal GABA transport. The only clinically approved compound with this mechanism of action is Tiagabine. Other GABA transporter subtypes have not been targeted with comparable selectivity and potency. We here review a comprehensive series of competitive inhibitors that provide information about the GABA recognition site and summarise the structure-activity relations in a ligand-based pharmacophore model that suggests how future compounds could be designed. Finally, some of the recent results on subtype-characterised competitive inhibitors and recent lipophilic aromatic GABA uptake inhibitors are reviewed.
Export Options
About this article
Cite this article as:
Hog Signe, Greenwood R. Jeremy, Madsen B. Karsten, Larsson M. Orla, Frolund Bente, Schousboe Arne, Krogsgaard-Larsen Povl and Clausen P. Rasmus, Structure-Activity Relationships of Selective GABA Uptake Inhibitors, Current Topics in Medicinal Chemistry 2006; 6 (17) . https://dx.doi.org/10.2174/156802606778249801
DOI https://dx.doi.org/10.2174/156802606778249801 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
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
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Exogenous Progesterone: A Potential Therapeutic Candidate in CNS Injury and Neurodegeneration
Current Medicinal Chemistry Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity
Current Pharmaceutical Design Clinical and Electroencephalographic Assessment of Cefepime During Treatment of Nosocomial Infections in Neurological Patients
Central Nervous System Agents in Medicinal Chemistry Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias
Current Pharmaceutical Design Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier
Current Neuropharmacology Editorial (Thematic Selection: Special Issue on Metabotropic Glutamate Receptors)
Current Neuropharmacology Bioinformatics and Drug Discovery
Current Topics in Medicinal Chemistry Biochemical Markers for Brain Injury Monitoring in Children with or without Congenital Heart Diseases
CNS & Neurological Disorders - Drug Targets Shining Light on an mGlu5 Photoswitchable NAM: A Theoretical Perspective
Current Neuropharmacology Understanding Genotypes and Phenotypes of the Mutations in Voltage- Gated Sodium Channel α Subunits in Epilepsy
CNS & Neurological Disorders - Drug Targets Potentials of ES Cell Therapy in Neurodegenerative Diseases
Current Pharmaceutical Design The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs
Current Medicinal Chemistry AED Strategy after Refractory Epilepsy Surgery
Current Pharmaceutical Design The Neuropharmacological Preclinical Effects of <i>Nigella sativa</i>: A Review
Current Bioactive Compounds Warming Up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin
Current Neurovascular Research Davunetide: Peptide Therapeutic in Neurological Disorders
Current Medicinal Chemistry Non-Celiac Gluten Sensitivity Triggers Gut Dysbiosis, Neuroinflammation, Gut-Brain Axis Dysfunction, and Vulnerability for Dementia
CNS & Neurological Disorders - Drug Targets Melatonin Therapy of Pediatric Sleep Disorders: Recent Advances, Why it Works, Who are the Candidates and How to Treat
Current Pediatric Reviews Lamotrigine as an Effective Treatment for Behavioral Disorders
Letters in Drug Design & Discovery Localised Delivery of Therapeutic Agents to CNS Malignancies: Old and New Approaches
Current Pharmaceutical Biotechnology