Voltage-Gated Ion Channels as Drug Targets

, by Triggle, David J.; Gopalakrishnan, Murali; Rampe, David; Zheng, Wei; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

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ISBN: 9783527312580 | 3527312587
Cover: Hardcover
Copyright: 3/17/2006

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Edited by the most prominent person in the field and top researchers at US pharmaceutical companies, this is a unique resource for drug developers and physiologists seeking a molecular-level understanding of ion channel pharmacology.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

1 Introduction — On Ion Channels

(6)

Murali Gopalakrishnan, David Rampe, David Triggle, and Wei Zheng

2 The Voltage-gated Ion Channel Superfamily

(12)

William A. Catterall

2.1 Introduction

(1)

2.2 Voltage-gated Sodium Channels

(2)

2.3 Voltage-gated Calcium Channels

(2)

2.4 Voltage-gated Potassium Channels

(1)

2.5 Inwardly Rectifying Potassium Channels

(1)

2.6 Common Aspects of Ion Channel Structure and Function

(1)

2.7 Condusions

(5)

3 State-dependent Drug Interactions with Ion Channels

(18)

Stefan I. McDonough and Bruce P. Bean

3.1 Introduction

(1)

3.2 Ion Channels as Drug Receptors

(1)

3.3 Ion Channels Adopt Multiple Conformations

(3)

3.4 Biophysics Meets Pharmacology State Dependence, Voltage Dependence, and the Modulated Receptor Model

(4)

3.5 Use Dependence

(2)

3.6 Physical Meaning of State Dependence

(1)

3.7 State Dependence in Drug Discovery

(2)

3.8 Future Directions for Ion Channel Drug Discovery

(4)

4 Assay Technologies: Techniques Available for Quantifying Drug–Channel Interactions

(28)

Derek Leishman and Gareth Waldron

4.1 Introduction

(2)

4.2 Patch Clamp

(9)

4.2.1 Basic Description of Technique

(3)

4.2.2 Advantages and Disadvantages of Manual Patch Clamp

(2)

4.2.3 Use of Patch Clamp for Quantification of Drug—Channel Effects

(3)

4.2.4 Caveats of Interpretations in Patch Clamp

(1)

4.3 Planar Patch Clamp

(2)

4.4 Two-electrode Voltage Clamp (TEVC) of Xenopus Oocytes

(1)

4.5 Membrane Potential Sensing Dyes

(5)

4.5.1 Basic Description of Membrane Potential-sensing Dyes

(2)

4.5.2 Advantages and Disadvantages of Membrane Potential-sensing Dyes

(3)

4.6 Binding

(1)

4.7 Ion Flux

(2)

4.7.1 Fluorescent Indicators of Ion Flux

(1)

4.7.2 Direct Measurement of Ion Flux

(1)

4.8 What Technologies Cannot be Used...Yet?

(1)

4.9 Summary

(5)

5 Calcium Channels

(86)

5.1 Overview of Voltage-gated Calcium Channels

(19)

Clinton Doering and Gerald Zamponi

5.1.1 Introduction

(1)

5.1.2 Native and Cloned Calcium Channels: Nomenclature and Classification

(1)

5.1.3 Distribution of VGCCs and their Physiological Roles

(3)

5.1.4 Structure of VGCC α1 Subunits

(3)

5.1.5 VGCC Modulation

(4)

5.1.6 VGCCs: Channelopathies and Pathologies

(1)

5.1.7 Summary

(7)

5.2 Drugs Active at T-type Ca²+ Channels

(16)

Thomas M. Connolly and James C. Barrow

5.2.1 Introduction

(1)

5.2.2 Methodology

(7)

5.2.3 Indications

(2)

5.2.4 Conclusions

(6)

5.3 L-type Calcium Channels

100

(22)

David J. Triggle

5.3.1 Introduction

100

(1)

5.3.2 Drugs that Interact with L-type Channels

100

(3)

5.3.3 Specific Drug Classes

103

(11)

5.3.4 Other Drug Classes Active at Cav1 Channels

114

(2)

5.3.5 Drug Interactions at Non-α-subunit Sites

116

(2)

5.3.6 Calcium Antagonism through Gene Delivery

118

(4)

5.4 N-type Calcium Channels

122

(29)

Terrance P. Snutch

5.4.1 Introduction

122

(1)

5.4.2 N-type Calcium Channel Pharmacology

123

(1)

5.4.3 Inorganic Cations

124

(1)

5.4.4 Peptide Blockers

125

(7)

5.4.5 Small Organic Molecule N-type Blockers

132

(8)

5.4.6 Conclusions

140

(11)

6 Sodium Channels

151

(42)

6.1 Molecular, Biophysical and Functional Properties of Voltage-gated Sodium Channels

151

(17)

Douglas S. Krafte, Mark Chapman, and Ken McCormack

6.1.1 Introduction

151

(1)

6.1.2 Primary and Tertiary Structure

152

(5)

6.1.3 Sodium Channel Expression

157

(2)

6.1.4 Biophysical Properties of Voltage-dependent Sodium Channels

159

(3)

6.1.5 Disease Association

162

(3)

6.1.6 Conclusions

165

(3)

6.2 Small Molecule Blockers of Voltage-gated Sodium Channels

168

(25)

Jesús E. González, Andreas P. Termin, and Dean M. Wilson

6.2.1 Drugs that Act on Sodium Channels

168

(2)

6.2.2 New Insights for Launched Compounds

170

(5)

6.2.3 Challenges of Current Agents

175

(1)

6.2.4 Compounds in Clinical Development

176

(4)

6.2.5 New Blockers in Discovery or Pre-clinical Stage

180

(6)

6.2.6 Emerging Indications and Future Directions

186

(7)

7 Potassium Channels

193

(188)

7.1 Potassium Channels: Overview of Molecular, Biophysical and Pharmacological Properties

193

(21)

Murali Gopalakrishnan, Char-Chang Shieh, and Jun Chen

7.1.1 Introduction

193

(1)

7.1.2 Classification and General Properties

194

(7)

7.1.3 Auxiliary Subunits

201

(1)

7.1.4 Crystal Structure

201

(3)

7.1.5 K+ Channels and Diseases

204

(1)

7.1.6 Ligands Interacting with K+ Channels

204

(2)

7.1.7 Ligand Binding Sites

206

(3)

7.1.8 Peptides and Toxins

209

(1)

7.1.9 Summary

210

(4)

7.2 Kv1.3 Potassium Channel: Physiology, Pharmacology and Therapeutic Indications

214

(61)

K. George Chandy, Heike Wulff Christine Becton, Peter A. Calabresi, George A. Gutman, and Michael Pennington

7.2.1 Introduction

214

(2)

7.2.2 Peptide Inhibitors of Kv1.3

216

(6)

7.2.3 Small Molecules Inhibitors of Kv1.3

222

(9)

7.2.4 Physiological Role of Kv1.3 and the Effects of Kv1.3 Blockers

231

(15)

7.2.5 Disease Indications

246

(5)

7.2.6 Conclusions

251

(24)

7.3 Drugs Active at Kv1.5 Potassium Channels [1]

275

(35)

Stefan Peukert and Heinz Gögelein

7.3.1 Structure of the Kv1.5 Channel

275

(1)

7.3.2 Pharmacological Significance of the Kv1.5 Channel

276

(2)

7.3.3 Known Drugs with Activity on Kv1.5

278

(5)

7.3.4 Structural Classes of New Kv1.5 Channel Blockers, their Structure–Activity Relationship and Pharmacology

283

(13)

7.3.5 Strategies in Lead Identification for Kv1.5 Blockers

296

(5)

7.3.6 Selectivity against other Ion Channels

301

(1)

7.3.7 Structural Basis for Kv1.5 Channel Block

302

(8)

7.4 Medicinal Chemistry of Ca²+-activated K+ Channel Modulators

310

(25)

Sean C. Turner and Char-Chang Shieh

7.4.1 Introduction

310

(8)

7.4.2 Medicinal Chemistry

318

(11)

7.4.3 Conclusions

329

(6)

7.5 Drugs Active at ATP-sensitive K+ Channels

335

(20)

William A. Carroll

7.5.1 Introduction

335

(2)

7.5.2 Mitochondrial KATP Channel Openers for Myocardial Ischemia

337

(2)

7.5.3 Sarc-KATP Blockers for Ventricular Arrhythmia

339

(1)

7.5.4 SUR1/Kir6.2 Openers for Diabetes and Hyperinsulinemia

340

(3)

7.5.5 SUR2B/Kir6.2 Openers for Overactive Bladder (OAB)

343

(5)

7.5.6 KATP Openers for Alopecia

348

(1)

7.5.7 Conclusions

348

(7)

7.6 Compounds that Activate KCNQ(2-5) Family of Potassium Ion Channels

355

(26)

Grant McNaughton-Smith and Alan D. Wickenden

7.6.1 Introduction

355

(1)

7.6.2 Flupirtine, Retigabine and Related Compounds

355

(5)

7.6.3 Benzanilide, Benzisoxazole and Indazole Derivatives

360

(2)

7.6.4 Oxindoles and Quinolinones

362

(2)

7.6.5 2,4-Disubstituted Pyrimidine-5-carboxamides Derivatives

364

(1)

7.6.6 Cinnamide Derivatives and Analogues

365

(5)

7.6.7 5-Carboxamide-thiazole Derivatives

370

(2)

7.6.8 Benzothiazoles as KCNQ(2-5) Agonists

372

(1)

7.6.9 Quinazolinones Derivatives

373

(2)

7.6.10 Salicylic Acid Derivatives

375

(1)

7.6.11 Melcofenamic Acid and Diclofenac-based KCNQ(2-5) Agonists

375

(2)

7.6.12 Summary

377

(4)

8 Genetic and Acquired Channelopathies

381

(86)

8.1 Inherited Disorders of Ion Channels

381

(47)

Kate Bracey and Dennis Wray

8.1.1 Introduction

381

(2)

8.1.2 Potassium Channels

383

(7)

8.1.3 Non-selective Cation Channels

390

(2)

8.1.4 Transient Receptor Potential (TRP) Channels

392

(1)

8.1.5 Voltage-gated Sodium Channels

393

(4)

8.1.6 Nonvoltage-gated Sodium Channels

397

(2)

8.1.7 Calcium Channels

399

(4)

8.1.8 Chloride Channels

403

(5)

8.1.9 Ligand-gated Channels

408

(4)

8.1.10 Conclusions

412

(16)

8.2 Structural and Ligand-based Models for HERG and their Application in Medicinal Chemistry

428

(16)

Yi Li, Giovanni Cianchetta, and Roy J. Vaz

8.2.1 Introduction: Perspective on the Necessity of Models

428

(2)

8.2.2 Structural Aspect of hERG Models

430

(1)

8.2.3 Ligand-based Chemometric Models

430

(4)

8.2.4 Ligand-based QSAR Models

434

(1)

8.2.5 Application of Models to Improve Selectivity Case Studies

434

(6)

8.2.6 Conclusions

440

(4)

8.3 Ion Channel Safety Issues in Drug Development

444

(23)

Armando A. Lagrutta and Joseph J. Salata

8.3.1 Introduction

444

(1)

8.3.2 Regulatory–Industry Relationship (ICH); Safety Pharmacology

444

(5)

8.3.3 Safety Issues Specific to the hERG Channel

449

(6)

8.3.4 "Integrated Risk Assessment" of Delayed Ventricular Repolarization

455

(2)

8.3.5 Beyond QT Prolongation

457

(2)

8.3.6 Issues Specific to Ion Channel Targets

459

(8)

Index

467

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Voltage-Gated Ion Channels as Drug Targets

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