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Phosphodiesterase Inhibitors
of: Clive Page, Christian Schudt, Gordon Dent (Eds.)
Elsevier Trade Monographs, 1996
ISBN: 9780080538815 , 228 Pages
Format: PDF, ePUB, Read online
Copy protection: DRM
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
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