Voltage-Gated Ion Channels as Drug Targets

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

• ISBN13: 9783527312580
• ISBN10: 3527312587
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-03-17
• Publisher: Wiley-VCH

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