Abstract
Selective agonists and antagonists for A3 adenosine receptors (ARs) are being explored for the treatment of a variety of disorders, including brain and heart ischemic conditions, cancer, and rheumatoid arthritis. This review covers both the structure activity relationships of nucleoside agonist ligands and selected antagonists acting at this receptor and the routes of synthesis. Highly selective agonists have been designed, using both empirical approaches and a semi-rational approach based on molecular modeling. The prototypical A3 agonists IB-MECA 10 and the more receptor-subtypeselective Cl-IB-MECA 11, both of which have affinity in binding to the receptor of ∼ 1 nM, have been used widely as pharmacological probes in the elucidation of the physiological role of this receptor. In addition to the exploration of the effects of structural modification of the adenine and ribose moieties on A3AR affinity, the effects of these structural changes on the intrinsic efficacy have also been studied in a systematic fashion. Key structural features determining A3AR interaction include the N6-benzyl group, 2-position substitution such as halo, substitution of ribose (e.g., the (N)- methanocarba ring system, various 2¢- and 3 ¢-substitutions and 4¢-thio substitution of oxygen). Conformational studies of the ribose moiety and its equivalents indicate that the ring oxygen is not required and the North (N) ring conformation is preferred in binding to the A3AR. Using these observations, a series of ring constrained (N)-methanocarba 5¢-uronamide derivatives was recently reported to be highly selective A3AR agonists, the most notable amongst them was MRS3558 113 having a Ki value in binding to the human A3 receptor of 0.3 nM.
Keywords: agonist, antagonist, purine, 7tm receptor, tissue protection, radioligand
Current Topics in Medicinal Chemistry
Title: Purine Derivatives as Ligands for A3 Adenosine Receptors
Volume: 5 Issue: 13
Author(s): Bhalchandra V. Joshi and Kenneth A. Jacobson
Affiliation:
Keywords: agonist, antagonist, purine, 7tm receptor, tissue protection, radioligand
Abstract: Selective agonists and antagonists for A3 adenosine receptors (ARs) are being explored for the treatment of a variety of disorders, including brain and heart ischemic conditions, cancer, and rheumatoid arthritis. This review covers both the structure activity relationships of nucleoside agonist ligands and selected antagonists acting at this receptor and the routes of synthesis. Highly selective agonists have been designed, using both empirical approaches and a semi-rational approach based on molecular modeling. The prototypical A3 agonists IB-MECA 10 and the more receptor-subtypeselective Cl-IB-MECA 11, both of which have affinity in binding to the receptor of ∼ 1 nM, have been used widely as pharmacological probes in the elucidation of the physiological role of this receptor. In addition to the exploration of the effects of structural modification of the adenine and ribose moieties on A3AR affinity, the effects of these structural changes on the intrinsic efficacy have also been studied in a systematic fashion. Key structural features determining A3AR interaction include the N6-benzyl group, 2-position substitution such as halo, substitution of ribose (e.g., the (N)- methanocarba ring system, various 2¢- and 3 ¢-substitutions and 4¢-thio substitution of oxygen). Conformational studies of the ribose moiety and its equivalents indicate that the ring oxygen is not required and the North (N) ring conformation is preferred in binding to the A3AR. Using these observations, a series of ring constrained (N)-methanocarba 5¢-uronamide derivatives was recently reported to be highly selective A3AR agonists, the most notable amongst them was MRS3558 113 having a Ki value in binding to the human A3 receptor of 0.3 nM.
Export Options
About this article
Cite this article as:
Joshi V. Bhalchandra and Jacobson A. Kenneth, Purine Derivatives as Ligands for A3 Adenosine Receptors, Current Topics in Medicinal Chemistry 2005; 5 (13) . https://dx.doi.org/10.2174/156802605774463079
DOI https://dx.doi.org/10.2174/156802605774463079 |
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
-
Macrophages in Immunopathology of Atherosclerosis: A Target for Diagnostics and Therapy
Current Pharmaceutical Design IgG Dimers in Multidonor-Derived Immunoglobulins: Aspects of Generation and Function
Current Pharmaceutical Design Gold Nanoparticle Based Systems in Genetics
Current Pharmacogenomics Small Molecule Antagonists of the Chemokine Receptor CCR5
Current Topics in Medicinal Chemistry GEMSP: A New Therapeutic Approach to Multiple Sclerosis
Central Nervous System Agents in Medicinal Chemistry Nummular Eczema: An Updated Review
Recent Patents on Inflammation & Allergy Drug Discovery Regulation of Angiogenesis by Macrophages, Dendritic Cells, and Circulating Myelomonocytic Cells
Current Pharmaceutical Design The Gut Microbiota and the Emergence of Autoimmunity: Relevance to Major Psychiatric Disorders
Current Pharmaceutical Design Crucial Protein Based Drug Targets and Potential Inhibitors for Osteoporosis: New Hope and Possibilities
Current Drug Targets The 2010 Patent Landscape for Spleen Tyrosine Kinase Inhibitors+
Recent Patents on Inflammation & Allergy Drug Discovery Role of Biomechanical Force in Stem Cell-Based Therapy for Cartilage Repair
Current Rheumatology Reviews Future Targets for Immune Therapy in Colitis?
Endocrine, Metabolic & Immune Disorders - Drug Targets Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α
Current Pharmaceutical Design Active Immunization Against Tumor Necrosis Factor-alpha Decreases Proinflammatory Cytokines, Oxidative Stress Mediators and Adhesion Molecules Risk Factors in Streptozotocin-induced Diabetic Rats
Endocrine, Metabolic & Immune Disorders - Drug Targets New Insights into Adipokines as Potential Biomarkers for Type-2 Diabetes Mellitus
Current Medicinal Chemistry Update on the Molecular Genetic Studies of Behcets Disease
Current Rheumatology Reviews Pharmacophore Modeling Methods in Focused Library Selection – Applications in the Context of a New Classification Scheme
Combinatorial Chemistry & High Throughput Screening Molecular Mechanisms, Emerging Etiological Insights and Models to Test Potential Therapeutic Interventions in Alzheimers Disease
Current Alzheimer Research Gender Disparities on Access to Care and Coronary Disease Management
Current Pharmaceutical Design TRAIL as Biomarker and Potential Therapeutic Tool for Cardiovascular Diseases
Current Drug Targets