Voltage-Gated Ion Channels as Drug Targets Methods & Principles in Medicinal Chemistry Series
Coordonnateurs : Triggle David J., Gopalakrishnan Murali, Rampe David, Zheng Wei
Directeurs de Collection : Mannhold Raimund, Kubinyi Hugo, Folkers Gerd
After an introduction to the topic, the authors evaluate the structure and function of ion channels, as well as related drug interaction. A section on assay technologies is followed by a section each on calcium, sodium and potassium channels. Further chapters cover genetic and acquired channelopathies, before the book closes with a look at safety issues in ion channel drug development.
For medicinal and pharmaceutical chemists, biochemists, molecular biologists and those working in the pharmaceutical industry.
Preface xi
1 Introduction – On Ion Channels 1
Murali Gopalakrishnan, David Rampe, David Triggle, and Wei Zheng
2 The Voltage-gated Ion Channel Superfamily 7
William A. Catterall
2.1 Introduction 7
2.2 Voltage-gated Sodium Channels 7
2.3 Voltage-gated Calcium Channels 9
2.4 Voltage-gated Potassium Channels 11
2.5 Inwardly Rectifying Potassium Channels 12
2.6 Common Aspects of Ion Channel Structure and Function 13
2.7 Conclusions 14
3 State-dependent Drug Interactions with Ion Channels 19
Stefan I. McDonough and Bruce P. Bean
3.1 Introduction 19
3.2 Ion Channels as Drug Receptors 20
3.3 Ion Channels Adopt Multiple Conformations 21
3.4 Biophysics Meets Pharmacology: State Dependence, Voltage Dependence, and the Modulated Receptor Model 24
3.5 Use Dependence 28
3.6 Physical Meaning of State Dependence 30
3.7 State Dependence in Drug Discovery 31
3.8 Future Directions for Ion Channel Drug Discovery 33
4 Assay Technologies: Techniques Available for Quantifying Drug–Channel Interactions 37
Derek Leishman and Gareth Waldron
4.1 Introduction 37
4.2 Patch Clamp 39
4.2.1 Basic Description of Technique 39
4.2.2 Advantages and Disadvantages of Manual Patch Clamp 42
4.2.3 Use of Patch Clamp for Quantification of Drug–Channel Effects 44
4.2.4 Caveats of Interpretations in Patch Clamp 47
4.3 Planar Patch Clamp 48
4.4 Two-electrode Voltage Clamp (TEVC) of Xenopus Oocytes 50
4.5 Membrane Potential Sensing Dyes 51
4.5.1 Basic Description of Membrane Potential-sensing Dyes 51
4.5.2 Advantages and Disadvantages of Membrane Potential-sensing Dyes 53
4.6 Binding 56
4.7 Ion Flux 57
4.7.1 Fluorescent Indicators of Ion Flux 57
4.7.2 Direct Measurement of Ion Flux 58
4.8 What Technologies Cannot be Used ... Yet? 59
4.9 Summary 60
5 Calcium Channels 65
5.1 Overview of Voltage-gated Calcium Channels 65
Clinton Doering and Gerald Zamponi
5.1.1 Introduction 65
5.1.2 Native and Cloned Calcium Channels: Nomenclature and Classification 65
5.1.3 Distribution of VGCCs and their Physiological Roles 66
5.1.4 Structure of VGCC α1 Subunits 69
5.1.5 VGCC Modulation 72
5.1.6 VGCCs: Channelopathies and Pathologies 76
5.1.7 Summary 77
5.2 Drugs Active at T-type Ca2+ Channels 84
Thomas M. Connolly and James C. Barrow
5.2.1 Introduction 84
5.2.2 Methodology 85
5.2.3 Indications 92
5.2.4 Conclusions 94
5.3 L-type Calcium Channels 100
David J. Triggle
5.3.1 Introduction 100
5.3.2 Drugs that Interact with L-type Channels 100
5.3.3 Specific Drug Classes 103
5.3.4 Other Drug Classes Active at CaV1 Channels 114
5.3.5 Drug Interactions at Non-α-subunit Sites 116
5.3.6 Calcium Antagonism through Gene Delivery 118
5.4 N-type Calcium Channels 122
Terrance P. Snutch
5.4.1 Introduction 122
5.4.2 N-type Calcium Channel Pharmacology 123
5.4.3 Inorganic Cations 124
5.4.4 Peptide Blockers 125
5.4.5 Small Organic Molecule N-type Blockers 132
5.4.6 Conclusions 140
6 Sodium Channels 151
6.1 Molecular, Biophysical and Functional Properties of Voltage-gated Sodium Channels 151
Douglas S. Krafte, Mark Chapman, and Ken McCormack
6.1.1 Introduction 151
6.1.2 Primary and Tertiary Structure 152
6.1.3 Sodium Channel Expression 157
6.1.4 Biophysical Properties of Voltage-dependent Sodium Channels 159
6.1.5 Disease Association 162
6.1.6 Conclusions 165
6.2 Small Molecule Blockers of Voltage-gated Sodium Channels 168
Jesús E. González, Andreas P. Termin, and Dean M. Wilson
6.2.1 Drugs that Act on Sodium Channels 168
6.2.2 New Insights for Launched Compounds 170
6.2.3 Challenges of Current Agents 175
6.2.4 Compounds in Clinical Development 176
6.2.5 New Blockers in Discovery or Pre-clinical Stage 180
6.2.6 Emerging Indications and Future Directions 186
7 Potassium Channels 193
7.1 Potassium Channels: Overview of Molecular, Biophysical and Pharmacological Properties 193
Murali Gopalakrishnan, Char-Chang Shieh, and Jun Chen
7.1.1 Introduction 193
7.1.2 Classification and General Properties 194
7.1.3 Auxiliary Subunits 201
7.1.4 Crystal Structure 201
7.1.5 K+ Channels and Diseases 204
7.1.6 Ligands Interacting with K+ Channels 204
7.1.7 Ligand Binding Sites 206
7.1.8 Peptides and Toxins 209
7.1.9 Summary 210
7.2 Kv1.3 Potassium Channel: Physiology, Pharmacology and Therapeutic Indications 214
K. George Chandy, Heike Wulff, Christine Beeton, Peter A. Calabresi, George A. Gutman, and Michael Pennington
7.2.1 Introduction 214
7.2.2 Peptide Inhibitors of Kv1.3 216
7.2.3 Small Molecules Inhibitors of Kv1.3 222
7.2.4 Physiological Role of Kv1.3 and the Effects of Kv1.3 Blockers 231
7.2.5 Disease Indications 246
7.2.6 Conclusions 251
7.3 Drugs Active at Kv1.5 Potassium Channels [1] 275
Stefan Peukert and Heinz Gögelein
7.3.1 Structure of the Kv1.5 Channel 275
7.3.2 Pharmacological Significance of the Kv1.5 Channel 276
7.3.3 Known Drugs with Activity on Kv1.5 278
7.3.4 Structural Classes of New Kv1.5 Channel Blockers, their Structure–Activity Relationship and Pharmacology 283
7.3.5 Strategies in Lead Identification for Kv1.5 Blockers 296
7.3.6 Selectivity against other Ion Channels 301
7.3.7 Structural Basis for Kv1.5 Channel Block 302
7.4 Medicinal Chemistry of Ca2+-activated K+ Channel Modulators 310
Sean C. Turner and Char-Chang Shieh
7.4.1 Introduction 310
7.4.2 Medicinal Chemistry 318
7.4.3 Conclusions 329
7.5 Drugs Active at ATP-sensitive K+ Channels 335
William A. Carroll
7.5.1 Introduction 335
7.5.2 Mitochondrial KATP Channel Openers for Myocardial Ischemia 337
7.5.3 Sarc-KATP Blockers for Ventricular Arrhythmia 339
7.5.4 SUR1/Kir6.2 Openers for Diabetes and Hyperinsulinemia 340
7.5.5 SUR2B/Kir6.2 Openers for Overactive Bladder (OAB) 343
7.5.6 KATP Openers for Alopecia 348
7.5.7 Conclusions 348
7.6 Compounds that Activate KCNQ(2–5) Family of Potassium Ion Channels 355
Grant McNaughton-Smith and Alan D. Wickenden
7.6.1 Introduction 355
7.6.2 Flupirtine, Retigabine and Related Compounds 355
7.6.3 Benzanilide, Benzisoxazole and Indazole Derivatives 360
7.6.4 Oxindoles and Quinolinones 362
7.6.5 2,4-Disubstituted Pyrimidine-5-carboxamides Derivatives 364
7.6.6 Cinnamide Derivatives and Analogues 365
7.6.7 5-Carboxamide-thiazole Derivatives 370
7.6.8 Benzothiazoles as KCNQ(2–5) Agonists 372
7.6.9 Quinazolinones Derivatives 373
7.6.10 Salicylic Acid Derivatives 375
7.6.11 Melcofenamic Acid and Diclofenac-based KCNQ(2–5) Agonists 375
7.6.12 Summary 377
8 Genetic and Acquired Channelopathies 381
8.1 Inherited Disorders of Ion Channels 381
Kate Bracey and Dennis Wray
8.1.1 Introduction 381
8.1.2 Potassium Channels 383
8.1.3 Non-selective Cation Channels 390
8.1.4 Transient Receptor Potential (TRP) Channels 392
8.1.5 Voltage-gated Sodium Channels 393
8.1.6 Nonvoltage-gated Sodium Channels 397
8.1.7 Calcium Channels 399
8.1.8 Chloride Channels 403
8.1.9 Ligand-gated Channels 408
8.1.10 Conclusions 412
8.2 Structural and Ligand-based Models for HERG and their Application in Medicinal Chemistry 428
Yi Li, Giovanni Cianchetta, and Roy J. Vaz
8.2.1 Introduction: Perspective on the Necessity of Models 428
8.2.2 Structural Aspect of hERG Models 430
8.2.3 Ligand-based Chemometric Models 430
8.2.4 Ligand-based QSAR Models 434
8.2.5 Application of Models to Improve Selectivity: Case Studies 434
8.2.6 Conclusions 440
8.3 Ion Channel Safety Issues in Drug Development 444
Armando A. Lagrutta and Joseph J. Salata
8.3.1 Introduction 444
8.3.2 Regulatory–Industry Relationship (ICH); Safety Pharmacology 444
8.3.3 Safety Issues Specific to the hERG Channel 449
8.3.4 “Integrated Risk Assessment” of Delayed Ventricular Repolarization 455
8.3.5 Beyond QT Prolongation 457
8.3.6 Issues Specific to Ion Channel Targets 459
Index 467
David Rampe is currently head of the Safety Pharmacology Department at Sanofi-Aventis Pharmaceuticals in Bridgewater, NJ, USA. Over the past 17 years he has worked in both the discovery and development areas of the pharmaceutical industry.
Wei Zheng is a Group Leader at the NIH Chemical Genomics Center. He was previously a Group Leader at Merck's centralized screening center. Over the past 12 years he has being working in the area of assay development and high throughput screening.
Murali Gopalakrishnan is a Project Leader in the Neuroscience Research Division of Abbott Laboratories, Illinois, USA. Over the past 12 years he has been engaged in various drug discovery programs in the areas of central nervous system, urology and pain.
Date de parution : 03-2006
Ouvrage de 492 p.
17.5x24.4 cm
Thème de Voltage-Gated Ion Channels as Drug Targets :
Mots-clés :
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