A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics (eBook)

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Anchor 1 4
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Chapter 1 15
From Hypertension (+) to Asthma: Interactions with the Adenosine A3 Receptor from a Personal Perspective 15
1.1 Introduction 15
1.2 Homage to the Discoverers of the A3 Receptor 15
1.3 Hypertension (+) 16
1.3.1 A Cardiovascular Response to Adenosine Receptor Ligands in the Rat That Is Not Mediated by A1 or A2 Receptors 16
1.3.2 The Hypotensive Response to A3 Receptor Ligands in the Rat Is Mast Cell Dependent 18
1.3.3 Comments on the Significance of Adenosine A3 Receptor-Induced, Mast Cell Degranulation In Vivo 18
1.4 Antagonists of the A3 Receptor for the Treatment of Asthma 19
1.4.1 Background and Concept 19
1.4.2 The Design and Synthesis of Novel Potent and Selective A3 Receptor Antagonists 21
1.4.3 An Example of the Species Selectivity of the A3 Receptor: The Receptor Responsible for Adenosine Augmentation of Med 21
1.4.4 The Design of Mixed A2B./A3 Receptor Antagonists and Their Biological Evaluation In Vitro 22
1.4.5 A Second Example of the Species Selectivity of the A3 Receptor: The In Vivo Evaluation of QAF805 23
1.5 Modelling the Airways Response to Adenosine: An Atypical Receptor Mechanism Mediates the Bronchoconstrictor Response to 24
1.6 By What Mechanism Does Adenosine Cause Bronchoconstriction in the Rat? 27
1.6.1 The Use of High Concentrations of CPA Reveals a Contribution to the Contractile Response of the Parenchymal Strip to 28
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 31
1.6.3 Does the Mechanism of the Contractile Response on the Parenchymal Strip Explain the Bronchoconstrictor Response to Ade 33
1.7 Conclusion 34
References 34
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Chapter 2 40
Thermodynamic Analysis in Drug–Receptor Binding: The A3 Adenosine Receptor 40
2.1 Introduction 40
2.2 Methods of Thermodynamic Measurement of Drug–Receptor Interaction 43
2.3 Affinity Constant Determination 43
2.4 Thermodynamic Parameters Determination 44
2.5 Representation of DG°, DH° and DS° Data 44
2.6 Binding Thermodynamics of A3 Adenosine Receptors 45
2.7 Binding Thermodynamics of G-Protein Coupled Receptors 50
2.8 Binding Thermodynamics of Ligand-Gated Ion Channel Receptors 53
2.9 Discussion 55
References 57
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Chapter 3 60
Pharmacology and Molecular Biology of A3 Adenosine Receptors 60
3.1 Introduction 60
3.2 Pharmacology 61
3.3 Tissue Distribution 62
3.4 Species Differences 62
3.5 Gene Structure 63
3.6 Transgenic and Knockout Animals 65
3.7 Conclusion 66
References 66
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Chapter 4 71
Regulation of Second Messenger Systems and Intracellular Pathways 71
4.1 Regulation of Second Messenger Systems Through G Protein Coupling 71
4.2 Regulation of Intracellular Pathways 73
4.2.1 The A3 Receptor and the Mitogen-Activated Protein Kinases (MAPKs) Signal Transduction Cascade 73
4.2.2 The A3 Receptor and the Phosphatidylinositol 3-Kinase/Protein Kinase B/Nuclear Factor-kB (PI3-K/AKT/NF-kB) Signal Tran 75
4.2.3 Cross Talk Between MAPK and PI3K/AKT Signalling Pathways, and Its Modulation by the A3 Receptor 76
4.2.4 The A3 Receptor and the Hypoxia-Inducible Factor 1 (HIF-1) 77
4.3 Conclusions 79
References 79
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Chapter 5 84
The Desensitisation as A3 Adenosine Receptor Regulation: Physiopathological Implications 84
5.1 A3 Adenosine Receptor Regulatory Mechanisms 84
Box 5.1 GPCR DesensitisationThe desensitisation of a GPCR response can be described as the loss of response subsequent to p 85
Box 5.2 GPCR InternalisationReceptor desensitisation, initiated by phosphorylation of the receptor, can be subsequently follow 91
5.2 Molecular Mechanisms 93
5.3 Physiopathological Implications 94
References 95
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Chapter 6 101
A3 Adenosine Receptor Agonists: History and Future Perspectives 101
6.1 Introduction to A3AR Agonists: Biological Effects and Therapeutic Prospects 102
6.2 A3AR Agonists: First Leads and Essential Screening Tools 106
6.2.1 Discovery of First A3AR Agonists 106
6.2.2 A3.AR Agonist Radioligands and Spectroscopic Probes 108
6.3 Detailed Structure Activity Relationship of Nucleosides as A3AR Agonists 109
6.3.1 Modulation of Affinity 109
6.3.1.1 Modification of the Nucleobase 109
6.3.1.2 Modification of the Ribose Moiety 115
6.3.2 Modulation of Efficacy by Nucleoside Modification 118
6.4 Non-nucleoside (e.g., Pyridine) A3AR Agonists 118
6.5 Allosteric Modulation of A3AR Agonist Affinity and Efficacy 120
6.6 Conclusions 123
References 124
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Chapter 7 129
A3 Adenosine Receptor Antagonists: History and Future Perspectives 129
7.1 Introduction 129
7.2 A3 AR Antagonists 130
7.2.1 Non-purine Heterocycles 130
7.2.1.1 Flavonoid Derivatives 130
7.2.1.2 1,4-Dihydropyridines and Pyridines 131
7.2.1.3 2-Mercaptopyrimidines 132
7.2.1.4 Triazoloquinazoline 133
7.2.1.5 Isoquinolines and Quinazolines 134
7.2.1.6 Thiazole and Thiadiazole 135
7.2.1.7 Pyrazoloquinolines 136
7.2.1.8 Triazoloquinoxalines 137
Triazolo[4,3-a]quinoxalines 137
Triazolo[1,5-a]quinoxalines 138
7.2.1.9 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines 138
7.2.1.10 Various Heterocycles 139
7.2.2 Purine Derivatives 140
7.2.2.1 Adenines 140
7.2.2.2 Triazolopurines 141
7.2.2.3 Tricyclic Xanthines 142
7.2.3 Nucleoside-Derived A3 AR Antagonists 144
7.3 Conclusions and Perspectives 149
References 149
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Chapter 8 156
Molecular Modeling and Reengineering of A3 Adenosine Receptors 156
8.1 Introduction 156
8.2 Homology Modeling of ARs 157
8.3 A3AR Models 160
8.4 Reengineered A3ARs: Neoceptors 165
8.5 Conclusions 166
References 167
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Chapter 9 170
Adenosine A3 Receptor Signaling in the Central Nervous System 170
9.1 Introduction 171
9.2 Distribution of A3.AR in the Central Nervous System (CNS) 172
9.3 The Roles of A3AR in the CNS 173
9.3.1 Role of A3AR in Memory and Cognition 173
9.3.2 Role of A3AR in Locomotion 174
9.3.3 Role of A3AR Receptors in Convulsions 175
9.3.4 Role of A3AR in Nociception 177
9.3.5 Role of A3AR in Mood and Affects 178
9.3.6 A3AR and Cerebral Blood Flow Regulation 178
9.4 Role of A3AR in Neurodegeneration 179
9.4.1 Role of A3AR in Hypoxia/Ischemia 179
9.4.2 A3AR and Neuroinflammation 183
9.4.2.1 Effects of A3AR in Astrocytes 183
9.4.2.2 Effects of A3AR in Microglia 185
9.5 Conclusions and Perspectives 186
References 186
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Chapter 10 194
Cardiovascular Biology of the A3 Adenosine Receptor 194
10.1 Cardiac Actions of the A3AR 194
10.2 Vascular Responses to the A3AR 196
10.3 Cardioprotective Actions of the A3AR 199
10.4 Summary and Future Directions 205
References 206
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Chapter 11 214
A3 Adenosine Receptor in the Pulmonary System 214
The Expression Pattern of A3 Adenosine Receptor in the Lung: Interspecies Differences and Functional Implications 214
11.2 A3 Adenosine Receptor in Reactive and Inflammatory Diseases of the Airways: Functional Role and Therapeutic Application 215
11.2.1 Pro and Anti-inflammatory Functions of Adenosine A3 Receptor in the Inflamed Airway (Table 11.1) 215
11.2.2 Mechanisms for the Pro and Anti-inflammatory Actions of Adenosine A3 Receptor During Airway Inflammation 217
11.2.3 Adenosine A3 Receptor in Asthma, COPD and Allergic Rhinitis 218
11.3 Adenosine A3 Receptor and Lung Injury: Functional and Clinical Implications 220
11.3.1 Adenosine A3 Receptor and Ischemia–Reperfusion-Induced Lung Injury 220
11.3.1.1 The Pathophysiology and molecular basis of Ischemia–Reperfusion-Induced Lung Injury 220
11.3.1.2 The Role of A3AR in the Attenuation of IR-Induced Lung Injury 221
11.3.1.3 Postulated Mechanisms of A3 Adenosine Receptor-Mediated Lung Protection 223
11.3.1.4 Other Adenosine Receptor Subtypes Involved in Lung Reperfusion Injury 224
11.3.2 Adenosine A3 Receptor in the Setting of Other Etiologies of Lung Injury 224
11.4 Adenosine A3 Receptor and Its Role in Modulation of Systemic and Pulmonary Vascular Tone 226
References 228
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Chapter 12 239
A3 Adenosine Receptor Regulation of Cells of the Immune System and Modulation of Inflammation 239
12.1 A3 Adenosine Receptor Effects on Neutrophil Function 239
12.2 A3 Adenosine Receptor Effects on Eosinophil Function 243
12.3 A3 Adenosine Receptor Effects on Lymphocyte Function 247
12.4 A3 Adenosine Receptor Effects on Monocyte-Macrophage Function 250
12.5 A3 Adenosine Receptor Effects on Dendritic Cell Function 252
12.6 Conclusions 255
References 256
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Chapter 13 261
Adenosine A3 Receptors in Muscle Protection 261
13.1 Biological Models and Relevant Pharmacology of Adenosine A3 Receptor Agonists and Antagonists 261
13.1.1 Skeletal Muscle Protection 262
13.1.2 Pharmacology of Adenosine Receptors and Relevance to Skeletal Muscle Protection 263
13.2 Role of Adenosine and Adenosine Receptor Subtypes in Muscle Protection 267
13.3 Mechanism of Protection and Working Model of A3 Receptor Signaling 273
13.4 Future Directions 281
13.5 Disclaimer 281
References 282
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Chapter 14 285
A3 Adenosine Receptors, HIF-1 Modulation and Atherosclerosis 285
14.1 Introduction 285
14.2 HIF-1 in the Pathogenesis of Atherosclerosis 286
14.3 Adenosine Receptors and HIF-1 288
14.4 A3 Adenosine Receptors, HIF-1 and Atherosclerosis 289
14.5 Conclusions 290
References 290
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Chapter 15 294
Rheumatoid Arthritis: History, Molecular Mechanisms and Therapeutic Applications 294
15.1 Rheumatoid Arthritis: Background 294
15.2 A3AR Agonists: Anti-inflammatory Agents for the Treatment of RA 295
15.3 Anti-inflammatory Effect of A3AR Agonists: Molecular Mechanism 296
15.4 The Clinical Development of CF101 as an Anti-inflammatory Drug to Combat RA 297
References 299
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Chapter 16 303
Agonists and Antagonists: Molecular Mechanisms and Therapeutic Applications 303
16.1 Cancer Cell Growth Is Driven by Cell Proliferation and Lack of Apoptosis 303
16.2 Over-Expression of A3AR Is a Characteristic of Tumor Cells 304
16.3 Tumors Respond to A3AR Agonists by Cell Cycle Arrest and Apoptosis 304
16.4 Hypoxia 307
16.5 Adenosine in Hypoxia 308
16.6 Tumor Cells in Hypoxia: Hypoxia-Inducible Factor-1, HIF-1 310
16.7 HIF-1 and the A3 Receptor 311
16.8 A3 Receptor and the Angiogenic Response 312
16.9 A3 Receptor and the Immunosuppression 313
16.10 Conclusions 314
References 314
Borea_Index_O 320