A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics

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Chapter 1

From Hypertension (+) to Asthma: Interactions with the Adenosine A3 Receptor from a Personal Perspective

1.1 Introduction

1.2 Homage to the Discoverers of the A3 Receptor

1.3 Hypertension (+)

1.3.1 A Cardiovascular Response to Adenosine Receptor Ligands in the Rat That Is Not Mediated by A1 or A2 Receptors

1.3.2 The Hypotensive Response to A3 Receptor Ligands in the Rat Is Mast Cell Dependent

1.3.3 Comments on the Significance of Adenosine A3 Receptor-Induced, Mast Cell Degranulation In Vivo

1.4 Antagonists of the A3 Receptor for the Treatment of Asthma

1.4.1 Background and Concept

1.4.2 The Design and Synthesis of Novel Potent and Selective A3 Receptor Antagonists

1.4.3 An Example of the Species Selectivity of the A3 Receptor: The Receptor Responsible for Adenosine Augmentation of Med

1.4.4 The Design of Mixed A2B./A3 Receptor Antagonists and Their Biological Evaluation In Vitro

1.4.5 A Second Example of the Species Selectivity of the A3 Receptor: The In Vivo Evaluation of QAF805

1.5 Modelling the Airways Response to Adenosine: An Atypical Receptor Mechanism Mediates the Bronchoconstrictor Response to

1.6 By What Mechanism Does Adenosine Cause Bronchoconstriction in the Rat?

1.6.1 The Use of High Concentrations of CPA Reveals a Contribution to the Contractile Response of the Parenchymal Strip to

1.6.2 2-Cl-IB-MECA Is a Silent Antagonist of the Mast Cell-Dependent Component of the Response to Adenosine and Reveals a Co

1.6.3 Does the Mechanism of the Contractile Response on the Parenchymal Strip Explain the Bronchoconstrictor Response to Ade

1.7 Conclusion

References

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Chapter 2

Thermodynamic Analysis in Drug–Receptor Binding: The A3 Adenosine Receptor

2.1 Introduction

2.2 Methods of Thermodynamic Measurement of Drug–Receptor Interaction

2.3 Affinity Constant Determination

2.4 Thermodynamic Parameters Determination

2.5 Representation of DG°, DH° and DS° Data

2.6 Binding Thermodynamics of A3 Adenosine Receptors

2.7 Binding Thermodynamics of G-Protein Coupled Receptors

2.8 Binding Thermodynamics of Ligand-Gated Ion Channel Receptors

2.9 Discussion

References

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Chapter 3

Pharmacology and Molecular Biology of A3 Adenosine Receptors

3.1 Introduction

3.2 Pharmacology

3.3 Tissue Distribution

3.4 Species Differences

3.5 Gene Structure

3.6 Transgenic and Knockout Animals

3.7 Conclusion

References

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Chapter 4

Regulation of Second Messenger Systems and Intracellular Pathways

4.1 Regulation of Second Messenger Systems Through G Protein Coupling

4.2 Regulation of Intracellular Pathways

4.2.1 The A3 Receptor and the Mitogen-Activated Protein Kinases (MAPKs) Signal Transduction Cascade

4.2.2 The A3 Receptor and the Phosphatidylinositol 3-Kinase/Protein Kinase B/Nuclear Factor-kB (PI3-K/AKT/NF-kB) Signal Tran

4.2.3 Cross Talk Between MAPK and PI3K/AKT Signalling Pathways, and Its Modulation by the A3 Receptor

4.2.4 The A3 Receptor and the Hypoxia-Inducible Factor 1 (HIF-1)

4.3 Conclusions

References

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Chapter 5

The Desensitisation as A3 Adenosine Receptor Regulation: Physiopathological Implications

5.1 A3 Adenosine Receptor Regulatory Mechanisms

Box 5.1 GPCR DesensitisationThe desensitisation of a GPCR response can be described as the loss of response subsequent to p

Box 5.2 GPCR InternalisationReceptor desensitisation, initiated by phosphorylation of the receptor, can be subsequently follow

5.2 Molecular Mechanisms

5.3 Physiopathological Implications

References

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Chapter 6

A3 Adenosine Receptor Agonists: History and Future Perspectives

6.1 Introduction to A3AR Agonists: Biological Effects and Therapeutic Prospects

6.2 A3AR Agonists: First Leads and Essential Screening Tools

6.2.1 Discovery of First A3AR Agonists

6.2.2 A3.AR Agonist Radioligands and Spectroscopic Probes

6.3 Detailed Structure Activity Relationship of Nucleosides as A3AR Agonists

6.3.1 Modulation of Affinity

6.3.1.1 Modification of the Nucleobase

6.3.1.2 Modification of the Ribose Moiety

6.3.2 Modulation of Efficacy by Nucleoside Modification

6.4 Non-nucleoside (e.g., Pyridine) A3AR Agonists

6.5 Allosteric Modulation of A3AR Agonist Affinity and Efficacy

6.6 Conclusions

References

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Chapter 7

A3 Adenosine Receptor Antagonists: History and Future Perspectives

7.1 Introduction

7.2 A3 AR Antagonists

7.2.1 Non-purine Heterocycles

7.2.1.1 Flavonoid Derivatives

7.2.1.2 1,4-Dihydropyridines and Pyridines

7.2.1.3 2-Mercaptopyrimidines

7.2.1.4 Triazoloquinazoline

7.2.1.5 Isoquinolines and Quinazolines

7.2.1.6 Thiazole and Thiadiazole

7.2.1.7 Pyrazoloquinolines

7.2.1.8 Triazoloquinoxalines

Triazolo[4,3-a]quinoxalines

Triazolo[1,5-a]quinoxalines

7.2.1.9 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines

7.2.1.10 Various Heterocycles

7.2.2 Purine Derivatives

7.2.2.1 Adenines

7.2.2.2 Triazolopurines

7.2.2.3 Tricyclic Xanthines

7.2.3 Nucleoside-Derived A3 AR Antagonists

7.3 Conclusions and Perspectives

References

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Chapter 8

Molecular Modeling and Reengineering of A3 Adenosine Receptors

8.1 Introduction

8.2 Homology Modeling of ARs

8.3 A3AR Models

8.4 Reengineered A3ARs: Neoceptors

8.5 Conclusions

References

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Chapter 9

Adenosine A3 Receptor Signaling in the Central Nervous System

9.1 Introduction

9.2 Distribution of A3.AR in the Central Nervous System (CNS)

9.3 The Roles of A3AR in the CNS

9.3.1 Role of A3AR in Memory and Cognition

9.3.2 Role of A3AR in Locomotion

9.3.3 Role of A3AR Receptors in Convulsions

9.3.4 Role of A3AR in Nociception

9.3.5 Role of A3AR in Mood and Affects

9.3.6 A3AR and Cerebral Blood Flow Regulation

9.4 Role of A3AR in Neurodegeneration

9.4.1 Role of A3AR in Hypoxia/Ischemia

9.4.2 A3AR and Neuroinflammation

9.4.2.1 Effects of A3AR in Astrocytes

9.4.2.2 Effects of A3AR in Microglia

9.5 Conclusions and Perspectives

References

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Chapter 10

Cardiovascular Biology of the A3 Adenosine Receptor

10.1 Cardiac Actions of the A3AR

10.2 Vascular Responses to the A3AR

10.3 Cardioprotective Actions of the A3AR

10.4 Summary and Future Directions

References

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Chapter 11

A3 Adenosine Receptor in the Pulmonary System

The Expression Pattern of A3 Adenosine Receptor in the Lung: Interspecies Differences and Functional Implications

11.2 A3 Adenosine Receptor in Reactive and Inflammatory Diseases of the Airways: Functional Role and Therapeutic Application

11.2.1 Pro and Anti-inflammatory Functions of Adenosine A3 Receptor in the Inflamed Airway (Table 11.1)

11.2.2 Mechanisms for the Pro and Anti-inflammatory Actions of Adenosine A3 Receptor During Airway Inflammation

11.2.3 Adenosine A3 Receptor in Asthma, COPD and Allergic Rhinitis

11.3 Adenosine A3 Receptor and Lung Injury: Functional and Clinical Implications

11.3.1 Adenosine A3 Receptor and Ischemia–Reperfusion-Induced Lung Injury

11.3.1.1 The Pathophysiology and molecular basis of Ischemia–Reperfusion-Induced Lung Injury

11.3.1.2 The Role of A3AR in the Attenuation of IR-Induced Lung Injury

11.3.1.3 Postulated Mechanisms of A3 Adenosine Receptor-Mediated Lung Protection

11.3.1.4 Other Adenosine Receptor Subtypes Involved in Lung Reperfusion Injury

11.3.2 Adenosine A3 Receptor in the Setting of Other Etiologies of Lung Injury

11.4 Adenosine A3 Receptor and Its Role in Modulation of Systemic and Pulmonary Vascular Tone

References

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Chapter 12

A3 Adenosine Receptor Regulation of Cells of the Immune System and Modulation of Inflammation

12.1 A3 Adenosine Receptor Effects on Neutrophil Function

12.2 A3 Adenosine Receptor Effects on Eosinophil Function

12.3 A3 Adenosine Receptor Effects on Lymphocyte Function

12.4 A3 Adenosine Receptor Effects on Monocyte-Macrophage Function

12.5 A3 Adenosine Receptor Effects on Dendritic Cell Function

12.6 Conclusions

References

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Chapter 13

Adenosine A3 Receptors in Muscle Protection

13.1 Biological Models and Relevant Pharmacology of Adenosine A3 Receptor Agonists and Antagonists

13.1.1 Skeletal Muscle Protection

13.1.2 Pharmacology of Adenosine Receptors and Relevance to Skeletal Muscle Protection

13.2 Role of Adenosine and Adenosine Receptor Subtypes in Muscle Protection

13.3 Mechanism of Protection and Working Model of A3 Receptor Signaling

13.4 Future Directions

13.5 Disclaimer

References

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Chapter 14

A3 Adenosine Receptors, HIF-1 Modulation and Atherosclerosis

14.1 Introduction

14.2 HIF-1 in the Pathogenesis of Atherosclerosis

14.3 Adenosine Receptors and HIF-1

14.4 A3 Adenosine Receptors, HIF-1 and Atherosclerosis

14.5 Conclusions

References

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Chapter 15

Rheumatoid Arthritis: History, Molecular Mechanisms and Therapeutic Applications

15.1 Rheumatoid Arthritis: Background

15.2 A3AR Agonists: Anti-inflammatory Agents for the Treatment of RA

15.3 Anti-inflammatory Effect of A3AR Agonists: Molecular Mechanism

15.4 The Clinical Development of CF101 as an Anti-inflammatory Drug to Combat RA

References

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Chapter 16

Agonists and Antagonists: Molecular Mechanisms and Therapeutic Applications

16.1 Cancer Cell Growth Is Driven by Cell Proliferation and Lack of Apoptosis

16.2 Over-Expression of A3AR Is a Characteristic of Tumor Cells

16.3 Tumors Respond to A3AR Agonists by Cell Cycle Arrest and Apoptosis

16.4 Hypoxia

16.5 Adenosine in Hypoxia

16.6 Tumor Cells in Hypoxia: Hypoxia-Inducible Factor-1, HIF-1

16.7 HIF-1 and the A3 Receptor

16.8 A3 Receptor and the Angiogenic Response

16.9 A3 Receptor and the Immunosuppression

16.10 Conclusions

References

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