Abstract
The γ-aminobutyric acid type A (GABAA) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride flux into the cell with subsequent hyperpolarization. Several GABAA receptor subunit isoforms have been cloned, the major isoform containing α, β, and γ subunits, and a regional heterogeneity associated with distinct physiological effects has been suggested. As a variety of allosteric ligands can modulate GABA-gated conductance changes through binding to distinct sites, the development of subtype-selective ligands may lead to the selective treatment of GABA system- associated pathology. In particular, the best characterized binding site is the benzodiazepine site (BzR), localized at the α/γ subunit interface, in which the α subunit is the main determinant of BzR ligand action selectivity. The α1-containing BzR have been proposed to be responsible for the sedative action; the α2 and/or the α3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the α5 subtype has been associated with cognition processes. The discovery of α-selective subtype ligands may help in the specific treatment of anxiety, sleep disorders, convulsions and memory deficits with fewer side effects. Selectivity may be achieved by two approaches: selective affinity or selective efficacy. Selective affinity needs a compound to bind with a higher affinity to one receptor subtype compared with another, whereas subtype-selective efficacy relies on a compound binding to all subtypes, but having different efficacies at various subtypes. The status of BzR ligands, subdivided on the basis of their main chemical structural features, is reviewed in relation to structure-activity relationships which determine their affinity or efficacy selectivity for a certain BzR subtype.
Keywords: GABAA/BzR complex, α-BzR isoforms, BzR ligands, affinity-selectivity, efficacy-selectivity, structure-activity relationships
Current Medicinal Chemistry
Title: GABAA/Bz Receptor Subtypes as Targets for Selective Drugs
Volume: 14 Issue: 25
Author(s): F. Da Settimo, S. Taliani, M. L. Trincavelli, M. Montali and C. Martini
Affiliation:
Keywords: GABAA/BzR complex, α-BzR isoforms, BzR ligands, affinity-selectivity, efficacy-selectivity, structure-activity relationships
Abstract: The γ-aminobutyric acid type A (GABAA) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride flux into the cell with subsequent hyperpolarization. Several GABAA receptor subunit isoforms have been cloned, the major isoform containing α, β, and γ subunits, and a regional heterogeneity associated with distinct physiological effects has been suggested. As a variety of allosteric ligands can modulate GABA-gated conductance changes through binding to distinct sites, the development of subtype-selective ligands may lead to the selective treatment of GABA system- associated pathology. In particular, the best characterized binding site is the benzodiazepine site (BzR), localized at the α/γ subunit interface, in which the α subunit is the main determinant of BzR ligand action selectivity. The α1-containing BzR have been proposed to be responsible for the sedative action; the α2 and/or the α3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the α5 subtype has been associated with cognition processes. The discovery of α-selective subtype ligands may help in the specific treatment of anxiety, sleep disorders, convulsions and memory deficits with fewer side effects. Selectivity may be achieved by two approaches: selective affinity or selective efficacy. Selective affinity needs a compound to bind with a higher affinity to one receptor subtype compared with another, whereas subtype-selective efficacy relies on a compound binding to all subtypes, but having different efficacies at various subtypes. The status of BzR ligands, subdivided on the basis of their main chemical structural features, is reviewed in relation to structure-activity relationships which determine their affinity or efficacy selectivity for a certain BzR subtype.
Export Options
About this article
Cite this article as:
Da Settimo F., Taliani S., Trincavelli L. M., Montali M. and Martini C., GABAA/Bz Receptor Subtypes as Targets for Selective Drugs, Current Medicinal Chemistry 2007; 14 (25) . https://dx.doi.org/10.2174/092986707782023190
DOI https://dx.doi.org/10.2174/092986707782023190 |
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
-
The Role of Neuroimaging in Our Understanding of the Suicidal Brain
CNS & Neurological Disorders - Drug Targets Phentermine and Topiramate Extended-Release for the Obesity: New Kids on the Block
Recent Patents on Cardiovascular Drug Discovery Exploiting High-Throughput Ion Channel Screening Technologies in Integrated Drug Discovery
Current Pharmaceutical Design Molecular Mechanisms of Cardiac Voltage-Gated Potassium Channelopathies
Current Pharmaceutical Design In-vitro Functionality of Clozapine Biphasic Release Minitablet Using Advanced Statistical Tools
Drug Delivery Letters Neurodegenerative Diseases of the Retina and Potential for Protection and Recovery
Current Neuropharmacology Calcium Channels and Prostate Cancer
Recent Patents on Anti-Cancer Drug Discovery Recent Advances on Neural Tube Defects with Special Reference to Valproic Acid
Endocrine, Metabolic & Immune Disorders - Drug Targets Glial Cells – The Key Elements of Alzheimer´s Disease
Current Alzheimer Research Chemistry and Biology of Cyperus scariosus: An Overview
Current Chemical Biology Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs
Current Topics in Medicinal Chemistry Exploring the Mechanism of Lingzhu San in Treating Febrile Seizures by Using Network Pharmacology
Combinatorial Chemistry & High Throughput Screening Stem Cell Behavior at Hypothermia: A Review Article
Current Stem Cell Research & Therapy Altered Homeostatic Functions in Reactive Astrocytes and Their Potential as a Therapeutic Target After Brain Ischemic Injury
Current Pharmaceutical Design Serotonin<sub>2c</sub> Receptor Constitutive Activity: In vivo Direct and Indirect Evidence and Functional Significance
Central Nervous System Agents in Medicinal Chemistry Evaluation of the Influence of the Conjugation Site of the Chelator Agent HYNIC to GLP1 Antagonist Radiotracer for Insulinoma Diagnosis
Current Radiopharmaceuticals Enantiopure 1,2,3-Triazolyl-β-amino Acids via Click Cycloaddition Reaction on Racemic Alkynyl Precursors Followed by Separation of Stereoisomers
Current Topics in Medicinal Chemistry Cyclooxygenase and Neuroinflammation in Parkinsons Disease Neurodegeneration
Current Neuropharmacology Meet Our Editorial Board Member:
Current Neuropharmacology Structure-Activity Relationships of Selective GABA Uptake Inhibitors
Current Topics in Medicinal Chemistry