Abstract
Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.
Keywords: Allosteric ligand, heterodimer, mGlu4 receptor, orthosteric ligand, positive allosteric modulator.
Current Topics in Medicinal Chemistry
Title:Chemical Biology of mGlu4 Receptor Activation: Dogmas, Challenges, Strategies and Opportunities
Volume: 14 Issue: 15
Author(s): Xinyan Huang, Elena Dale, Robbin M. Brodbeck and Dario Doller
Affiliation:
Keywords: Allosteric ligand, heterodimer, mGlu4 receptor, orthosteric ligand, positive allosteric modulator.
Abstract: Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.
Export Options
About this article
Cite this article as:
Huang Xinyan, Dale Elena, Brodbeck M. Robbin and Doller Dario, Chemical Biology of mGlu4 Receptor Activation: Dogmas, Challenges, Strategies and Opportunities, Current Topics in Medicinal Chemistry 2014; 14 (15) . https://dx.doi.org/10.2174/1568026614666140902143830
DOI https://dx.doi.org/10.2174/1568026614666140902143830 |
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
-
NF-κB Blockers Gifted by Mother Nature: Prospectives in Cancer Cell Chemosensitization
Current Pharmaceutical Design Intracellular Trafficking of MDR Transporters and Relevance of SNPs
Current Topics in Medicinal Chemistry Pharmacological Intervention of Cyclooxygenase-2 and 5-Lipoxygenase Pathways. Impact on Inflammation and Cancer
Current Pharmaceutical Design The Urokinase-type Plasminogen Activator and the Generation of Inhibitors of Urokinase Activity and Signaling
Current Pharmaceutical Design Alterations within the Osteo-Hematopoietic Niche in MDS and their Therapeutic Implications
Current Pharmaceutical Design Magnetite Nanostructures with Applications in Cancer Therapy
Current Proteomics Pathobiology and Prevention of Cancer Chemotherapy-Induced Bone Growth Arrest, Bone Loss, and Osteonecrosis
Current Molecular Medicine Emulsomes Meet S-layer Proteins: An Emerging Targeted Drug Delivery System
Current Pharmaceutical Biotechnology Metallic Nanoparticles as SERS Agents for Biomolecular Imaging
Current Pharmaceutical Biotechnology PACAP is Implicated in the Stress Axes
Current Pharmaceutical Design The Anti-cancer Actions of Vitamin D
Anti-Cancer Agents in Medicinal Chemistry Polymorphisms in Methotrexate Pathways: What Is Clinically Relevant, What Is Not, and What Is Promising
Current Drug Metabolism From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Identification of AHSA1 as a Potential Therapeutic Target for Breast Cancer: Bioinformatics Analysis and <i>in vitro</i> Studies
Current Cancer Drug Targets Anti-VEGF Mediated Immunomodulatory Role of Phytochemicals: Scientific Exposition for Plausible HCC Treatment
Current Drug Targets Nanoparticle Based Delivery of Protease Inhibitors to Cancer Cells
Current Medicinal Chemistry Epigenetic Remodeling of Chromatin Architecture: Exploring Tumor Differentiation Therapies in Mesenchymal Stem Cells and Sarcomas
Current Stem Cell Research & Therapy Analytical Methods for Determination of CO and CO2 and their Applicability in Biological Studies
Current Pharmaceutical Analysis Patent Selections
Recent Patents on Biomarkers The MDM2 Inhibitor Nutlins as an Innovative Therapeutic Tool for the Treatment of Haematological Malignancies
Current Pharmaceutical Design