Adenosine Receptors in Health and Disease (eBook)

Introduction to Adenosine Receptors as Therapeutic Targets 14
1 Introduction 17
2 Sources and Fate of Extracellular Adenosine 20
3 Adenosine Receptor Structure 21
4 Regulation of Adenosine Receptors 23
5 Adenosine Receptor Agonists and Antagonists in Preclinical and Clinical Trials 23
5.1 Adenosine Receptor Agonists 24
5.2 Adenosine Receptor Antagonists 26
5.3 Radioligands for In Vivo Imaging 29
6 Allosteric Modulation of Adenosine Receptors 30
7 Genetic Deletion of Adenosine Receptors 31
8 Conclusions 31
References 32
A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers 38
1 Introduction 41
2 A1 Adenosine Receptor Antagonists 41
2.1 KW3902 42
2.2 BG9928 50
2.3 SLV320 56
3 A1 Adenosine Receptor Agonists 58
3.1 Intravenous Antiarrhythmic Agents: Tecadenoson, Selodenoson, Phenylsulfide, Phenylethers, PJ-875 60
3.2 Insulin-Sensitizing Agents: GR79236, ARA, CVT-3619 62
3.3 Angina Agents: Capadenoson (Nonnucleoside: BAY 68--4986) 65
4 Allosteric Enhancers 65
4.1 Neuropathic Pain: T-62 65
5 Conclusion 66
References 67
Recent Developments in Adenosine A2A Receptor Ligands 72
1 Adenosine A2A Receptor Agonists 73
1.1 Adenosine 73
1.2 Ribose-Modified Adenosine Derivatives 76
1.3 Purine-Modified Adenosine Derivatives 77
1.3.1 2- or N6-Substituted Adenosine Derivatives 78
1.4 Ribose- and Purine-Modified Adenosine Derivatives 80
1.4.1 2-Substituted NECA Derivatives 80
1.4.2 Ribose- and Purine-Modified NECA Derivatives 83
1.5 Agonist Radioligands 84
1.6 Partial Agonists 84
2 Adenosine A2A Receptor Antagonists 85
2.1 Xanthine Derivatives 86
2.2 Adenine Derivatives and Related Heterocyclic Compounds 91
2.3 Heterocyclic Compounds Unrelated to Adenine or Xanthine 97
2.4 Antagonist Radioligands 97
References 99
Recent Developments in A2B Adenosine Receptor Ligands 112
1 Introduction 114
2 A2B Adenosine Receptor Antagonists 115
2.1 Xanthine-Based Antagonists 115
2.2 Deazaxanthine-Based Antagonists 122
2.3 Adenine-Based Antagonists 124
2.4 2-Aminopyridine-Based Antagonists 125
2.5 Bipyrimidine-Based Antagonists 126
2.6 Pyrimidone-Based Antagonists 127
2.7 Imidazopyridine-Based Antagonists 127
2.8 Pyrazine-Based Antagonists 128
2.9 Pyrazolo-Triazolo-Pyrimidine-Based Antagonists 131
3 Conclusion 132
References 132
Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering 136
1 Introduction 139
2 A3AR Agonists 141
2.1 Substitution of the Adenine Moiety of Adenine Nucleosides 145
2.1.1 N6 Position 145
2.1.2 Adenine 2 Position 147
2.2 Ribose Modifications 148
2.2.1 Modification of Ribose Hydroxyl Groups 148
2.2.2 Modification of the Pentose Ring 149
2.3 Nonadenine Nucleosides and Nonnucleosides as A3AR Agonists 151
2.4 Further Optimization of A3AR Agonists Using Multiple Modifications 151
3 A3AR Antagonists 152
3.1 Recent Developments in Nonpurine Heterocycles 154
3.1.1 Thiazole and Thiadiazole 154
3.1.2 Pyrazoloquinolines 155
3.1.3 Triazoloquinoxalines 155
3.1.4 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines 156
3.1.5 Various Heterocycles 158
3.2 Purine Derivatives 159
3.2.1 Adenines 159
3.2.2 Triazolopurines 160
3.2.3 Tricyclic Xanthines 160
3.3 Nucleoside-Derived A3AR Antagonists 162
4 Engineering of the A3AR to Avoid Side Effects of Conventional Synthetic Agonists 164
5 Conclusions 164
References 165
Adenosine Receptors and the Heart: Role in Regulation of Coronary Blood Flow and Cardiac Electrophysiology 173
1 General Background: The Adenosine Hypothesis 176
2 Adenosine and Coronary Regulation 177
3 Endothelium-Dependent and Endothelium-Independent Regulation 177
4 Baseline Coronary Flow Control 178
5 Second-Messenger Systems 179
5.1 cAMP--MAPK 179
5.2 PLC--PKC 180
5.3 Other Second Messengers 180
5.4 K+ Channels 181
6 Insight from Adenosine Receptor Gene-Modified Models 182
6.1 A2AAR KO Mouse 182
6.2 A2BAR KO Mouse 184
6.3 A1AR and A3AR KO Mouse 184
7 Clinical Application of Selective A2AAR Agonists for the Detection of Coronary Artery Disease 185
8 Cardiac Electrophysiology of Adenosine: Recent Developments 186
8.1 Introduction 186
8.2 Basic Aspects 187
8.2.1 Negative Chronotropic Action 187
8.2.2 Negative Dromotropic Action 188
8.2.3 Adenosine's Effects on Atrial and Ventricular Myocardium 189
8.3 Clinical Aspects 189
8.3.1 Supraventricular Tachycardias 189
8.3.2 Ventricular Tachycardia/Fibrillation 190
8.4 Adenosine as a Diagnostic Tool 191
8.5 Future Prospects 192
References 192
Adenosine Receptors and Reperfusion Injury of the Heart 201
1 Introduction 202
2 Cardioprotection with Tonic A1AR Agonism: A1AR Overexpression 203
3 Cardioprotection via Preischemic AR Activation: A Role in PC Responses 204
3.1 Adenosine as a Preischemic Trigger of PC 205
3.1.1 AR-Triggered Pharmacological PC 205
3.1.2 ARs as Intrinsic Triggers of IPC 206
3.1.3 Evidence from Gene-Modified Models 208
3.2 AR Activity During Ischemia 208
4 Reperfusion Injury and ARs in Experimental Studies 210
4.1 Effects of the A2AAR During Reperfusion 211
4.2 Effects of A1 and A3ARs During Reperfusion 213
4.3 Emerging Roles for the A2BAR During Reperfusion 214
5 Reperfusion Injury and ARs in Human Myocardium 215
6 Impact of Age and Disease 217
References 217
Adenosine Receptors and Inflammation 227
1 Introduction 229
1.1 Adenosine Production and Metabolism 229
1.2 Adenosine Receptors 231
2 Adenosine Receptors on Immune Cells 232
2.1 Neutrophils 232
2.2 Monocytes and Macrophages 233
2.3 Dendritic Cells 235
2.4 Lymphocytes 236
2.5 Mast Cells 238
2.6 Eosinophils 238
2.7 Endothelial Cells 239
3 Regulation of Adenosine Receptor Expression in Inflammatory Environments 240
3.1 Adenosine Receptor Desensitization 242
4 Adenosine Receptor Contributions to the Regulation of Inflammation 243
4.1 A1AR and Inflammatory Responses 243
4.1.1 Historical Perspective 243
4.1.2 Proinflammatory Effects 243
4.1.3 Anti-inflammatory Effects 247
4.2 A2AAR and Inflammatory Responses 250
4.2.1 Historical Perspective 250
4.2.2 Anti-inflammatory Effects 251
4.2.3 Detrimental Aspects of A2AAR Engagement 253
4.3 A2BAR and Inflammatory Responses 255
4.3.1 Historical Perspective 255
4.3.2 Anti-inflammatory Effects 255
4.3.3 Proinflammatory Effects 257
4.4 A3AR and Inflammatory Responses 259
4.4.1 Historical Perspective 259
4.4.2 Anti-inflammatory Effects 260
4.4.3 A3AR in Disease Progression and Potential Agonist Therapies 260
4.4.4 Proinflammatory Effects 261
4.4.5 Potential Use of Antagonist in the Treatment of Inflammation 262
5 Conclusions 263
References 264
A1 Adenosine Receptor: Role in Diabetes and Obesity 282
1 Introduction 283
2 A1AR Expression in Adipose Tissue 286
3 Adipocyte A1AR Function and Regulation in Disease Models 287
4 Inhibition of Lipolysis: A Therapeutic Approach 289
4.1 A1AR Agonists 290
4.2 A1AR Antagonists 292
5 Challenges for the Development of A1AR Agonists as Therapeutic Agents 293
5.1 Receptor Density and Distribution 293
5.2 Receptor Desensitization 294
6 Possible Solutions to the Challenges Involved in Developing A1AR Agonists as Antilipolytic Agents 295
6.1 Receptor Reserve 296
6.2 Partial Agonists 296
6.2.1 Organ and Response Selectivity 297
6.2.2 Less Receptor Desensitization than Full Agonist 298
6.2.3 Functions as an Antagonist of a Full Agonist 298
7 Conclusions 298
References 299
A3 Adenosine Receptor: Pharmacology and Role in Disease 307
1 Cloning, Distribution and Gene Structure of the A3 Adenosine Receptor (A3AR) 309
2 A3 Adenosine Receptor (A3AR) Signal Transduction 311
2.1 A3 Adenosine Receptor (A3AR) Desensitization 313
3 A3 Adenosine Receptor (A3AR) and Ischemic Brain Disease 315
4 A3 Adenosine Receptor (A3AR) and Ischemic Heart Disease 318
5 A3 Adenosine Receptor (A3AR) and Inflammatory Diseases 320
5.1 A3 Adenosine Receptor (A3AR) and Autoimmune Inflammatory Diseases 323
6 Conclusion 326
References 327
Adenosine Receptors and Asthma 338
1 Adenosine: An Important Signaling Molecule in Asthma 340
1.1 Adenosine Metabolism 342
1.2 Adenosine-Induced Bronchoconstriction, Airway Inflammation, and Airway Remodeling 344
2 Adenosine Receptors in Asthma 346
2.1 A1 Adenosine Receptors and Asthma 348
2.2 A2A Adenosine Receptors and Asthma 354
2.3 A2B Adenosine Receptors and Asthma 356
2.4 A3 Adenosine Receptors and Asthma 360
3 Conclusions and Future Directions 362
References 362
Adenosine Receptors, Cystic Fibrosis, and Airway Hydration 372
1 Cystic Fibrosis and Airway Ion Transport 374
2 Regulation of Airway Cl- Transport by Adenosine and Related Nucleotides 377
3 Repercussions of Altered Adenosine Levels in the Airway 383
4 Conclusions 386
References 386
Adenosine Receptors in Wound Healing, Fibrosis and Angiogenesis 391
1 Introduction 392
2 Role of Adenosine in Neovascularization 393
2.1 Regulation of Neovascularization in the Skin 395
2.2 Regulation of Neovascularization in the Heart and Skeletal Muscles 395
2.3 Regulation of Neovascularization in the Lung 396
2.4 Regulation of Neovascularization in Tumors 396
3 Role of Adenosine in Fibrosis 397
3.1 A2A Adenosine Receptor Agonists Promote Wound Healing 397
3.2 A2A Adenosine Receptor Occupancy Stimulates Fibroblast Matrix Production 398
3.3 A2B Adenosine Receptor Occupancy Regulates Fibroblast Collagen Production and Fibrosis 399
3.4 A1 Adenosine Receptors Play a Role in Cardiac and Vascular Fibrosis 399
4 Conclusion 400
References 400
Adenosine Receptors and Cancer 406
1 Introduction 409
2 A1 Adenosine Receptor 409
3 A2A Adenosine Receptor 413
3.1 The A2AAR: Protector of Host Tissue, Protector of Tumors 413
3.2 Tumors Evade the Immune System by Inhibiting Immune Cell Function 413
3.3 The A2AAR Negatively Regulates Immune Responses 414
3.4 Adenosine Protects Tumors from Immune Destruction 415
3.5 A2AAR Antagonism as a Means of Enhancing Immunotherapy 417
4 A2B Adenosine Receptors 417
5 A3 Adenosine Receptor 421
5.1 Overexpression of the A3AR in Tumor Versus Normal Adjacent Tissues 422
5.2 In Vitro Studies 424
5.2.1 Effect of Low-Concentration A3AR Agonists on Tumor Cell Growth 424
5.2.2 Effect of High-Concentration A3AR Agonists on Tumor Cell Growth 425
5.3 In Vivo Studies 426
5.3.1 Melanoma 430
5.3.2 Colon Carcinoma 430
5.3.3 Prostate Carcinoma 430
5.3.4 Hepatocellular Carcinoma 430
5.3.5 Potentiation of Natural Killer Cell Activity 431
5.3.6 Chemoprotective Effect 431
5.4 Mechanisms of Action for the Anticancer Activity of the A3AR 431
5.4.1 Direct Effect of A3AR Agonists on Tumor Cells: Deregulation of the NF-bold0mu mumu kkequationkkkkB and Wnt Signaling Pathways 432
5.4.2 A3AR Agonists as Myeloprotective Agents 434
6 Anticancer Activity of A3AR Antagonists 436
7 Summary and Conclusions 438
References 439
Adenosine Receptors and the Kidney 449
1 Introduction 451
2 Vascular Effects of Adenosine in Kidney Cortex and Medulla 452
2.1 Activation of A1AR Lowers Glomerular Filtration Rate 452
2.2 Factors Modulating Adenosine-Induced Cortical Vasoconstriction 454
2.3 Activation of A2AR Induces Medullary Vasodilation 454
2.4 Adenosine is a Mediator of Tubuloglomerular Feedback via Activation of A1AR 455
3 Activation of A1AR Inhibits Renin Secretion 457
4 Differential Effects of Adenosine on Fluid and Electrolyte Transport 457
4.1 Activation of A1AR Increases Reabsorption in the Proximal Tubule 457
4.2 Activation of A1AR Inhibits Reabsorption in Medullary Thick Ascending Limb 458
4.3 Effects of Adenosine on Transport in Distal Convolution and Cortical Collecting Duct 458
4.4 Activation of A1AR Counteracts Vasopressin Effects in Inner Medullary Collecting Duct 459
5 Adenosine and Metabolic Control of Kidney Function 459
6 Adenosine and Acute Renal Failure 459
6.1 Radiocontrast Media-Induced Acute Renal Failure: Theophylline and A1AR Antagonists Induce Protective Effects 461
6.2 Ischemia-Reperfusion Injury 461
6.2.1 Theophylline Induces Protective Effects 462
6.2.2 Adenosine Induces Protective Effects via A1AR and A2AR 463
7 A1AR Antagonists in the Treatment of Cardiorenal Failure 465
7.1 Animal Studies 465
7.2 Human Studies 467
References 468
Adenosine Receptors and the Central Nervous System 477
1 Introduction 480
2 Adenosine as a Ubiquitous Neuromodulator 481
3 Manipulation of Endogenous Levels of Adenosine and its Neuromodulation 484
4 Distribution of ARs in the Central Nervous System and the Effect of Aging 487
5 Adenosine as a Modulator of Other Neuromodulators 490
5.1 Interactions with G-Protein-Coupled Receptors 490
5.1.1 Dopamine Receptors 490
5.1.2 Neuropeptides 492
5.1.3 Metabotropic Glutamate Receptors 493
5.1.4 Cannabinoid Receptors 494
5.1.5 A1, A2A and A3ARs 495
5.1.6 P2 Purinoceptors 497
5.2 Interaction with Ionotropic Receptors 498
5.2.1 Modulation of NMDA and AMPA Receptors by A1 and A2 ARs 498
5.2.2 Nicotinic Acetylcholine Receptors 499
5.3 Interaction with Receptors for Neurotrophic Factors 500
6 Hypoxia and Ischemia 504
6.1 Adenosine and Control of Synaptic Transmission During Hypoxia 504
6.2 Adenosine and Control of Ventilation 505
6.2.1 Adenosine and Respiration in the Newborn 506
7 Role of ARs in Pain 506
8 Caffeine and ARs 508
8.1 Influence on Brain Function and Dysfunction 510
8.1.1 Sleep 510
8.1.2 Epilepsy 511
8.1.3 Cognition, Learning, and Memory 512
8.1.4 Alzheimer's Disease 513
8.1.5 Anxiety 514
8.1.6 Depression 514
8.1.7 Schizophrenia 515
8.1.8 Huntington's Disease 516
8.1.9 Parkinson's Disease 517
9 Drug Addiction and Substances of Abuse 517
9.1 Opioids 518
9.2 Cocaine 519
9.3 Amphetamine 520
9.4 Cannabinoids 520
9.5 Ethanol 521
10 Concluding Remarks 521
References 522
Adenosine Receptors and Neurological Disease: Neuroprotection and Neurodegeneration 541
1 Introduction 544
2 Relevant General Features of Adenosine Receptor Actions 544
2.1 A1 Adenosine Receptors 544
2.2 A2A Adenosine Receptors 545
2.3 A2B Adenosine Receptors 546
2.4 A3 Adenosine Receptors 547
2.5 Receptor Interactions 547
2.6 Anti-inflammatory Effects 550
3 Role of Adenosine Receptors in Brain Cell Survivaland in Neurodegenerative Diseases 551
3.1 A1 Adenosine Receptors and Neuroprotection 551
3.2 A2A Adenosine Receptors and Neuroprotection 552
3.3 A2B Adenosine Receptors and Neuroprotection 556
3.4 A3 Adenosine Receptors and Neuroprotection 556
3.5 Adenosine Receptors and Therapeutic Possibilities 556
3.6 Molecular Basis of Neuroprotection 557
3.7 Trophic Activity 559
4 Aging and Alzheimer's Disease 559
4.1 Changes of Adenosine Receptors with Aging 559
4.2 Alterations of Adenosine Receptors in Alzheimer's Patients 560
4.3 Adenosine Receptors and Cognition 561
4.4 The Enigma of Propentofylline 564
4.5 Adenosine, Homocysteinuria and Alzheimer's Disease 564
4.6 Genetic Studies 565
5 Creutzfeldt--Jakob Disease 565
6 Lesch--Nyhan Syndrome 566
7 Multiple Sclerosis 566
8 Huntington's Disease 567
8.1 Adenosine Receptors in HD 568
9 Cerebral Ischemia and Reperfusion: Stroke 570
9.1 Role of A1 Adenosine Receptors 570
9.2 Role of A2 Adenosine Receptors 571
9.3 Role of A3 Adenosine Receptors 573
9.4 Time Course of Protection Induced by Adenosine Receptor Ligands 573
9.5 Acute Versus Chronic Administration 574
9.6 Therapeutic Implications of Preconditioning 575
10 Prospects for Adenosine Receptor-Based Therapeutics 576
References 577
Adenosine A2A Receptors and Parkinson's Disease 594
1 Introduction 596
2 Parkinson's Disease 596
3 Treatment of PD and Limitations of Therapy 598
4 Basal Ganglia Organization 599
4.1 Localization of A2AARs in Basal Ganglia 599
4.2 Function of A2AARs in Basal Ganglia 600
4.3 Role of Globus Pallidus A2A Adenosine Receptors 602
5 Motor-Behavioral Effects of A2AAR Antagonists in Animal Models of Parkinson's Disease 603
5.1 Effects of Acute A2AAR Antagonism on Motor Deficits 603
5.2 Efficacy of A2AAR Antagonists in Relieving Parkinsonian Tremor and Muscular Rigidity 604
5.3 Effects of Chronic A2AAR Antagonism on Motor Complicationsand Dyskinesia 605
5.4 Effects of Acute and Chronic A2AAR Antagonism on Biochemical Parameters 607
5.5 Biochemical Changes in Extrastriatal Basal Ganglia Areas 607
6 Clinical Actions of Adenosine A2AAR Antagonists 608
7 Future Directions 611
7.1 Effects on Cognition 611
7.2 Neuroprotective Potential 612
8 Conclusions 613
References 613
Adenosine Receptor Ligands and PET Imaging of the CNS 621
1 Introduction 623
2 Development of PET Radioligands 625
2.1 Adenosine A1 Receptor Ligands 626
2.2 Adenosine A2A Receptor Ligands 628
2.3 Adenosine A3 Receptor Ligands 632
2.4 Ligands for the Adenosine Uptake Site 632
2.5 Radiosynthesis 633
3 Experimental Studies 633
4 Clinical Studies 634
4.1 Adenosine A1 Receptor Imaging 634
4.2 Adenosine A2A Receptor Imaging 637
5 Conclusion 639
References 639
Index 647