Voltage-Gated Ion Channels as Drug Targets

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1 Voltage-Gated Ion Channels as Drug Targets Edited by David J. Triggle, Murali Gopalakrishnan, David Rampe, and Wei Zheng WILEY- VCH WILEY-VCH Verlag GmbH & Co. KGaA

2 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 Voltage-gated Sodium Channels Voltage-gated Calcium Channels Voltage-gated Potassium Channels Inwardly Rectifying Potassium Channels Common Aspects of Ion Channel Structure and Function Conclusions 14 3 State-dependent Drug Interactions with Ion Channels 19 Stefan I. McDonough and Bruce P. Bean 3.1 Introduction Ion Channels as Drug Receptors Ion Channels Adopt Multiple Conformations Biophysics Meets Pharmacology: State Dependence, Voltage Dependence, and the Modulated Receptor Model Use Dependence Physical Meaning of State Dependence State Dependence in Drug Discovery Future Directions for Ion Channel Drug Discovery 33 Voltage-Gated Ion Channels as Drug Targets. Edited by D. Triggle Copyright 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN

3 VI Contents 4 Assay Technologies: Techniques Available for Quantifying Drug-Channel Interactions 37 Derek Leishman and Gareth Waldron 4.1 Introduction Patch Clamp Basic Description of Technique Advantages and Disadvantages of Manual Patch Clamp Use of Patch Clamp for Quantification of Drug-Channel Effects Caveats of Interpretations in Patch Clamp Planar Patch Clamp Two-electrode Voltage Clamp (TEVC) of Xenopus Oocytes Membrane Potential Sensing Dyes Basic Description of Membrane Potential-sensing Dyes Advantages and Disadvantages of Membrane Potential-sensing Dyes Binding Ion Flux Fluorescent Indicators of Ion Flux Direct Measurement of Ion Flux What Technologies Cannot be Used... Yet? Summary 60 5 Calcium Channels Overview of Voltage-gated Calcium Channels 65 Clinton Doering and Gerald Zamponi Introduction Native and Cloned Calcium Channels: Nomenclature and Classification Distribution of VGCCs and their Physiological Roles Structure of VGCC a, Subunits VGCC Modulation VGCCs: Channelopathies and Pathologies Summary Drugs Active at T-type Ca 2+ Channels 84 Thomas M. Connolly and James C. Barrow Introduction Methodology Indications Conclusions 94

4 VII 5.3 L-type Calcium Channels 200 David J. Triggle Introduction Drugs that Interact with L-type Channels Specific Drug Classes Other Drug Classes Active at Ca v l Channels Drug Interactions at Non-a-subunit Sites Calcium Antagonism through Gene Delivery N-type Calcium Channels 122 Terrance P. Snutch Introduction N-type Calcium Channel Pharmacology Inorganic Cations Peptide Blockers Small Organic Molecule N-type Blockers Conclusions Sodium Channels Molecular, Biophysical and Functional Properties of Voltage-gated Sodium Channels 151 Douglas S. Krafie, Mark Chapman, and Ken McCormack Introduction Primary and Tertiary Structure Sodium Channel Expression Biophysical Properties of Voltage-dependent Sodium Channels Disease Association Conclusions Small Molecule Blockers of Voltage-gated Sodium Channels 168 Jesus E. Gonzalez, Andreas P. Termin, and Dean M. Wilson Drugs that Act on Sodium Channels New Insights for Launched Compounds Challenges of Current Agents Compounds in Clinical Development New Blockers in Discovery or Pre-clinical Stage Emerging Indications and Future Directions 286

5 VIM Contents 7 Potassium Channels Potassium Channels: Overview of Molecular, Biophysical and Pharmacological Properties 193 Murali Gopalakrishnan, Char-Chang Shieh, and Jun Chen Introduction Classification and General Properties Auxiliary Subunits Crystal Structure K + Channels and Diseases Ligands Interacting with K + Channels Ligand Binding Sites Peptides and Toxins Summary Kvl.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 Introduction Peptide Inhibitors of Kvl Small Molecules Inhibitors of Kvl Physiological Role of Kvl.3 and the Effects of Kvl.3 Blockers Disease Indications Conclusions Drugs Active at Kvl.5 Potassium Channels [1] 275 Stefan Peukert and Heinz Gogelein Structure of the Kvl.5 Channel Pharmacological Significance of the Kvl.5 Channel Known Drugs with Activity on Kvl Structural Classes of New Kvl.5 Channel Blockers, their Structure-Activity Relationship and Pharmacology Strategies in Lead Identification for Kvl.5 Blockers Selectivity against other Ion Channels Structural Basis for Kvl.5 Channel Block Medicinal Chemistry of Ca 2+ -activated K + Channel Modulators Sean C. Turner and Char-Chang Shieh 7 A.I Introduction Medicinal Chemistry Conclusions

6 IX Drugs Active at ATP-sensitive K + Channels 335 William A. Carroll Introduction 335 Mitochondrial K ATP Channel Openers for Myocardial Ischemia 337 Sarc-K ATP Blockers for Ventricular Arrhythmia 339 SUR1/Kir6.2 Openers for Diabetes and Hyperinsulinemia 340 SUR2B/Kir6.2 Openers for Overactive Bladder (OAB) 343 K ATP Openers for Alopecia 348 Conclusions 348 Compounds that Activate KCNQ(2-5) Family of Potassium Ion Channels 355 Grant McNaughton-Smith and Alan D. Wickenden Introduction 355 Flupirtine, Retigabine and Related Compounds 355 Benzanilide, Benzisoxazole and Indazole Derivatives 360 Oxindoles and Quinolinones 362 2,4-Disubstituted Pyrimidine-5-carboxamides Derivatives 364 Cinnamide Derivatives and Analogues Carboxamide-thiazole Derivatives 370 Benzothiazoles as KCNQ(2-5) Agonists 372 Quinazolinones Derivatives 373 Salicylic Acid Derivatives 375 Melcofenamic Acid and Diclofenac-based KCNQ(2-5) Agonists 375 Summary 377 Genetic and Acquired Channelopathies 381 Inherited Disorders of Ion Channels 381 Kate Bracey and Dennis Wray Introduction 381 Potassium Channels 383 Non-selective Cation Channels 390 Transient Receptor Potential (TRP) Channels 392 Voltage-gated Sodium Channels 393 Nonvoltage-gated Sodium Channels 397 Calcium Channels 399 Chloride Channels 403 Ligand-gated Channels 408 Conclusions 412

7 8.2 Structural and Ligand-based Models for HERG and their Application in Medicinal Chemistry 428 Yi Li, Giovanni Cianchetta, and Roy J. Vaz Introduction: Perspective on the Necessity of Models Structural Aspect of herg Models Ligand-based Chemometric Models Ligand-based QSAR Models Application of Models to Improve Selectivity: Case Studies Conclusions Ion Channel Safety Issues in Drug Development 444 Armando A. Lagrutta and Joseph J.' Salata Introduction Regulatory-Industry Relationship (ICH); Safety Pharmacology Safety Issues Specific to the herg Channel "Integrated Risk Assessment" of Delayed Ventricular Repolarization Beyond QT Prolongation Issues Specific to Ion Channel Targets 459 Index 467

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