Abstract
γ-aminobutyric acid (GABA) plays important roles in the central nervous system, acting as a neurotransmitter on both ionotropic ligand-gated Cl--channels, and metabotropic G-protein coupled receptors (GPCRs). These two types of receptors called GABAA (and C) and GABAB are the targets of major therapeutic drugs such as the anxiolytic benzodiazepines, and antispastic drug baclofen (lioresal®), respectively. Although the multiplicity of GABAA receptors offer a number of possibilities to discover new and more selective drugs, the molecular characterization of the GABAB receptor revealed a unique, though complex, heterodimeric GPCR. High throughput screening strategies carried out in pharmaceutical industries, helped identifying new compounds positively modulating the activity of the GABAB receptor. These molecules, almost devoid of apparent activity when applied alone, greatly enhance both the potency and efficacy of GABAB agonists. As such, in contrast to baclofen that constantly activates the receptor everywhere in the brain, these positive allosteric modulators induce a large increase in GABAB-mediated responses only WHERE and WHEN physiologically needed. Such compounds are then well adapted to help GABA to activate its GABAB receptors, like benzodiazepines favor GABAA receptor activation. In this review, the way of action of these molecules will be presented in light of our actual knowledge of the activation mechanism of the GABAB receptor. We will then show that, as expected, these molecules have more pronounced in vivo responses and less side effects than pure agonists, offering new potential therapeutic applications for this new class of GABAB ligands.
Keywords: Baclofen, anxiety, drug addiction, allosteric modulators, class C GPCRs
Current Neuropharmacology
Title: Allosteric Modulators of GABAB Receptors: Mechanism of Action and Therapeutic Perspective
Volume: 5 Issue: 3
Author(s): Jean-Philippe Pin and Laurent Prezeau
Affiliation:
Keywords: Baclofen, anxiety, drug addiction, allosteric modulators, class C GPCRs
Abstract: γ-aminobutyric acid (GABA) plays important roles in the central nervous system, acting as a neurotransmitter on both ionotropic ligand-gated Cl--channels, and metabotropic G-protein coupled receptors (GPCRs). These two types of receptors called GABAA (and C) and GABAB are the targets of major therapeutic drugs such as the anxiolytic benzodiazepines, and antispastic drug baclofen (lioresal®), respectively. Although the multiplicity of GABAA receptors offer a number of possibilities to discover new and more selective drugs, the molecular characterization of the GABAB receptor revealed a unique, though complex, heterodimeric GPCR. High throughput screening strategies carried out in pharmaceutical industries, helped identifying new compounds positively modulating the activity of the GABAB receptor. These molecules, almost devoid of apparent activity when applied alone, greatly enhance both the potency and efficacy of GABAB agonists. As such, in contrast to baclofen that constantly activates the receptor everywhere in the brain, these positive allosteric modulators induce a large increase in GABAB-mediated responses only WHERE and WHEN physiologically needed. Such compounds are then well adapted to help GABA to activate its GABAB receptors, like benzodiazepines favor GABAA receptor activation. In this review, the way of action of these molecules will be presented in light of our actual knowledge of the activation mechanism of the GABAB receptor. We will then show that, as expected, these molecules have more pronounced in vivo responses and less side effects than pure agonists, offering new potential therapeutic applications for this new class of GABAB ligands.
Export Options
About this article
Cite this article as:
Pin Jean-Philippe and Prezeau Laurent, Allosteric Modulators of GABAB Receptors: Mechanism of Action and Therapeutic Perspective, Current Neuropharmacology 2007; 5 (3) . https://dx.doi.org/10.2174/157015907781695919
DOI https://dx.doi.org/10.2174/157015907781695919 |
Print ISSN 1570-159X |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6190 |
Call for Papers in Thematic Issues
Advances in Neuroinflammation and Neuroprotection: Mechanisms and Therapeutic Frontiers
It offers a comprehensive exploration of neuroinflammatory and neuroprotective pathways that play central roles in a range of neurological disorders, including stroke, traumatic brain injury, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. This issue invites research on the cellular and molecular mechanisms driving neuroinflammation, such as the roles of ...read more
Advances in paediatric and adult brain cancers: emerging targets and treatments
Brain tumors are the most common solid tumors affecting children and adolescents, with up to 5,000 children diagnosed per year. Pediatric brain tumors, because of their location, are often untreatable and their clinical management can cause significant long-term impairment to intellectual and neurological function with epilepsy and neurodegeneration. Other than ...read more
Emotion (Dys)regulation: An integration of Pharmacological, Neurobiological, and Psychological Frameworks
Emotion regulation is a critical aspect of mental well-being and interpersonal relationships. To fully understand and effectively address emotion regulation, an integrative approach that considers pharmacological, neurobiological, and psychological frameworks is essential. Pharmacological interventions, such as medications targeting neurotransmitter imbalances, can play a significant role in managing emotional dysregulation. Understanding ...read more
Enhancing Neuropharmacology with Home Cage Monitoring, Advanced Delivery and Stimulation Technologies, and Artificial Intelligence
Home cage monitoring (HCM) technologies have revolutionized neuropharmacological research by enabling continuous, non-invasive observation of rodents in their natural environments. Complementary advancements such as 24/7 continuous drug delivery systems (e.g., implantable pumps) and wireless neurostimulation methods—including optogenetics—offer precise methods for modulating neural activity and administering pharmacological agents without disrupting the ...read more

- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
-
Desensitization of 5-HT-1A Somatodentritic Receptors in Tryptophan Treated and Co-treated Rats Induced by Methylphenidate
Current Clinical Pharmacology The Evolution of Schizophrenia: A Model for Selection by Infection, with a Focus on NAD
Current Pharmaceutical Design Curcumin Activates Erythrocyte Membrane Acetylcholinesterase
Letters in Drug Design & Discovery Subject Index
Adolescent Psychiatry <i>In Vivo</i> Longitudinal Monitoring of Changes in the Corpus Callosum Integrity During Disease Progression in a Mouse Model of Alzheimer’s Disease
Current Alzheimer Research Method Development and Validation of a Novel UHPLC Coupled with MS/MS System for the Estimation of Brivaracetam in Human (K2EDTA) Plasma Samples and its Application to Pharmacokinetic Study
Current Pharmaceutical Analysis Synthesis and Evaluation of Anticonvulsant Activities of Triazole- Incorporated Benzothiazoles
Letters in Drug Design & Discovery Medication-precipitated Seizure in Psychiatric Patients: Typical vs. Atypical Antipsychotics
Current Psychopharmacology Histone Deacetylase Inhibitors: Therapeutic Agents and Research Tools for Deciphering Motor Neuron Diseases
Current Medicinal Chemistry Brain Permeable Nanoparticles
Recent Patents on CNS Drug Discovery (Discontinued) An Overview of Galenic Preparation Methods for Medicinal Cannabis
Current Bioactive Compounds Nuezhenide Exerts Anti-Inflammatory Activity through the NF-κB Pathway
Current Molecular Pharmacology A panoramic view of chronic liver diseases and natural remedies reported in Traditional Persian Medicine
Current Pharmaceutical Design Inquiries into the Biological Significance of Transmembrane AMPA Receptor Regulatory Protein (TARP) γ−8 Through Investigations of TARP γ−8 Null Mice§
CNS & Neurological Disorders - Drug Targets Huntingtons Disease: The Value of Transcranial Meganetic Stimulation
Current Medicinal Chemistry Editorial (Hot Topic: Organic Solute Transporters and Diseases: Potential Therapeutic Targets)
Current Molecular Pharmacology Exploring the Role of Gene Therapy for Neurological Disorders
Current Gene Therapy Screen-Printed Biosensors in Drug Analysis
Current Pharmaceutical Analysis Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology
Current Neuropharmacology Editorial
Current Pediatric Reviews