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9783527312580

Voltage-Gated Ion Channels as Drug Targets

by ; ; ; ; ; ;
  • ISBN13:

    9783527312580

  • ISBN10:

    3527312587

  • Edition: 1st
  • Format: Hardcover
  • Copyright: 2006-03-17
  • Publisher: Wiley-VCH

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Summary

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.

Author Biography

David J. Triggle is a Professor for Pharmacy at the State University of New York at Buffalo, USA, where he is investigating drug-receptor interactions and has specialized in ion channel pharmacology. He is the author of several books, has contributed around 350 papers, chapters and reviews, and has presented over 1,000 lectures worldwide. <br> <br> 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. <br> <br> 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. <br> <br> 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. <br> <br>

Table of Contents

Preface XI
1 Introduction — On Ion Channels 1(6)
Murali Gopalakrishnan, David Rampe, David Triggle, and Wei Zheng
2 The Voltage-gated Ion Channel Superfamily 7(12)
William A. Catterall
2.1 Introduction
7(1)
2.2 Voltage-gated Sodium Channels
7(2)
2.3 Voltage-gated Calcium Channels
9(2)
2.4 Voltage-gated Potassium Channels
11(1)
2.5 Inwardly Rectifying Potassium Channels
12(1)
2.6 Common Aspects of Ion Channel Structure and Function
13(1)
2.7 Condusions
14(5)
3 State-dependent Drug Interactions with Ion Channels 19(18)
Stefan I. McDonough and Bruce P. Bean
3.1 Introduction
19(1)
3.2 Ion Channels as Drug Receptors
20(1)
3.3 Ion Channels Adopt Multiple Conformations
21(3)
3.4 Biophysics Meets Pharmacology State Dependence, Voltage Dependence, and the Modulated Receptor Model
24(4)
3.5 Use Dependence
28(2)
3.6 Physical Meaning of State Dependence
30(1)
3.7 State Dependence in Drug Discovery
31(2)
3.8 Future Directions for Ion Channel Drug Discovery
33(4)
4 Assay Technologies: Techniques Available for Quantifying Drug–Channel Interactions 37(28)
Derek Leishman and Gareth Waldron
4.1 Introduction
37(2)
4.2 Patch Clamp
39(9)
4.2.1 Basic Description of Technique
39(3)
4.2.2 Advantages and Disadvantages of Manual Patch Clamp
42(2)
4.2.3 Use of Patch Clamp for Quantification of Drug—Channel Effects
44(3)
4.2.4 Caveats of Interpretations in Patch Clamp
47(1)
4.3 Planar Patch Clamp
48(2)
4.4 Two-electrode Voltage Clamp (TEVC) of Xenopus Oocytes
50(1)
4.5 Membrane Potential Sensing Dyes
51(5)
4.5.1 Basic Description of Membrane Potential-sensing Dyes
51(2)
4.5.2 Advantages and Disadvantages of Membrane Potential-sensing Dyes
53(3)
4.6 Binding
56(1)
4.7 Ion Flux
57(2)
4.7.1 Fluorescent Indicators of Ion Flux
57(1)
4.7.2 Direct Measurement of Ion Flux
58(1)
4.8 What Technologies Cannot be Used...Yet?
59(1)
4.9 Summary
60(5)
5 Calcium Channels 65(86)
5.1 Overview of Voltage-gated Calcium Channels
65(19)
Clinton Doering and Gerald Zamponi
5.1.1 Introduction
65(1)
5.1.2 Native and Cloned Calcium Channels: Nomenclature and Classification
65(1)
5.1.3 Distribution of VGCCs and their Physiological Roles
66(3)
5.1.4 Structure of VGCC α1 Subunits
69(3)
5.1.5 VGCC Modulation
72(4)
5.1.6 VGCCs: Channelopathies and Pathologies
76(1)
5.1.7 Summary
77(7)
5.2 Drugs Active at T-type Ca²+ Channels
84(16)
Thomas M. Connolly and James C. Barrow
5.2.1 Introduction
84(1)
5.2.2 Methodology
85(7)
5.2.3 Indications
92(2)
5.2.4 Conclusions
94(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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