Phosphodiesterase Inhibitors (eBook)

Front Cover 1
Phosphodiesterase Inhibitors 4
Copyright Page 5
Contents 6
Contributors 10
Series Preface 14
Preface 16
Chapter 1. Identification and Quantification of PDE Isoenzymes and Subtypes by Molecular BiologicaI Methods 18
1. Introduction 18
2. The PDE Gene Family 18
3. Molecular Cloning and Localization of the Mammalian PDEs 20
4. Summary 31
5. References 31
Chapter 2. Analysis of PDE Isoenzyme Profiles in Cells and Tissues by Pharmacological Methods 38
1. Introduction 38
2. Analysis of PDE Isoenzyme Activities in Cells and Tissues 39
3. Regulation of PDE Isoenzyme Activities 47
4. Conclusions 51
5. References 51
Chapter 3. Effects of Theophylline and Non-selective Xanthine Derivatives on PDE Isoenzymes and Cellular Function 58
1. Introduction 58
2. Inhibition of PDE 59
3. Effects on Cell Function 61
4. Summary and Directions for Future Research 72
5. References 73
Chapter 4. Ca 2+/Calmodulin-dependent Cyclic Nucleotide Phosphodiesterase (PDE1) 82
1. Introduction 82
2. Purification and Characterization 83
3. Isoenzymes of CaM-PDE 83
4. Activity in Cancer Cells 91
5. Conclusions 91
6. Acknowledgements 91
7. References 92
Chapter 5. EHNA as an Inhibitor of PDE2: a Pharmacological and Biochemical Study in Cardiac Myocytes 98
1. Introduction 98
2. Methods 99
3. Results 100
4. Discussion 103
5. Acknowledgements 104
6. References 104
Chapter 6. cGMP-Inhibited Phosphodiesterases (PDE3) 106
1. Introduction 106
2. Purification and Characterization 106
3. Molecular Cloning and Domain Organization 109
4. Structure/Function Relationships 110
5. Pharmacology and Potential Therapeutic Usage of PDE3 Inhibitors 113
6. Therapeutic Usage of PDE3 Inhibitors 118
7. Acknowledgements 118
8. References 118
Chapter 7. Interaction of PDE4 Inhibitors with Enzymes and Cell Functions 128
1. The PDE4 Isoenzyme Family 128
2. Pharmacology of PDE4 Inhibitors 132
3. Adverse Effects of PDE4 Inhibitors 136
4. PDE4 Alterations in Allergic Diseases 136
5. Summary and Future Directions 137
6. References 138
Chapter 8. Inhibition of Phosphodiesterase Isoenzymes and Cell Function by Selective PDE5 Inhibitors 144
1. Introduction 144
2. Scientific Rationale for PDE5 Inhibitors 144
3. PDE5 Inhibition and Vasorelaxation 145
4. Potential Therapeutic Applications of PDE5 Inhibitors 147
5. Additional Indications for PDE5 Inhibitors 148
6. Newer PDE5 Inhibitors 148
7. Combination Inhibitors 149
8. Summary 149
9. Acknowledgement 149
10. References 149
Chapter 9. Design and Synthesis of Xanthines and Cyclic GMP Analogues as Potent Inhibitors of PDE5 152
1. Introduction 152
2. Strategy for the Design of PDE5 Inhibitors 153
3. Synthesis of IBMX and cGMP Analogues as PDE Inhibitors 153
4. Selectivity of the IBMX Analogues as PDE Inhibitors 155
5. cGMP Analogues as PDE Inhibitors 159
6. Smooth Muscle Relaxation by IBMX and cGMP Analogues 160
7. Conclusions 161
8. Acknowledgements 162
9. References 162
Chapter 10. Enzymatic and Functional Aspects of Dual-selective PDE3/4 Inhibitors 164
1. Introduction 164
2. Dual Inhibitors of PDE3/4 for Asthma Therapy 165
3. Preclinical Pharmacology of PDE3/4 Inhibitors 166
4. Clinical Experience with PDE3/4 Inhibitors 169
5. Conclusions 174
6. References 175
Chapter 11. An Isoform-selective Inhibitor of Cyclic AMP-specific Phosphodiesterase (PDE4) with Anti-inflammatory Properties 178
1. Introduction 178
2. Materials and Methods 179
3. Results 182
4. Discussion 186
5. Acknowledgements 187
6. References 187
Chapter 12. Characterization of Different States of PDE4 by Rolipram and RP 73401 190
1. Introduction 190
2. Pharmacology of RP 73401 190
3. Interactions of RP 73401 and Rolipram with Eosinophil PDE4 192
4. Inhibition of PDE4 from Other Cells and Tissues 195
5. Possible Therapeutic Implications 198
6. Conclusions 199
7. References 199
Chapter 13. MolecularAspects of Inhibitor Interaction with PDE4 202
1. Introduction 202
2. Molecular Biology of PDE4 207
3. Rolipram-Binding Site 210
4. Mechanistic Enzymology 212
5. Structure-Activity Relationships 216
6. Summary and Conclusions 219
7. References 220
Glossary 226
Key to Illustrations 236
Index 242
Color Plate Section 246