Transporters as Drug Targets

Content: Preface XIII    A Personal Foreword XVII    1 Insights into Transporter Classifications: an Outline of Transporters as Drug Targets 1 Michael Viereck, Anna Gaulton, and Daniela Digles    1.1 Introduction 1    1.2 Available Transporter Classifications 2    1.3 Function versus Sequence Similarity 7    1.4 Merged Top-Level Transporter Classification 7    1.5 Choice and Design of the New ChEMBL Classification 11    1.6 Transporter as Drug Targets 12    1.7 Drug Targets in the SLC Classification 15    1.8 Conclusions 17    Acknowledgment 17    References 18    2 New Trends in Antidepressant Drug Research 21 Benny Bang-Andersen, Klaus P. Bogeso, Jan Kehler, and Connie Sanchez    2.1 Introduction 21    2.2 Reuptake Blockers 26    2.3 Multimodal Drugs 36    2.4 Conclusions 42    List of Abbreviations 42    References 43    3 The Molecular Basis of the Interaction Between Drugs and Neurotransmitter Transporters 53 Harald H. Sitte, Thomas Stockner, and Michael Freissmuth    3.1 Introduction 53    3.2 Crystal Structures of SLC6 Transporters 55    3.3 The Binding Site Proper 60    3.4 The Transport Cycle 61    3.5 Conclusions and Perspectives 63    Acknowledgments 64    References 64    4   -Aminobutyric Acid and Glycine Neurotransmitter Transporters 69 Petrine Wellendorph, Julie Jacobsen, Jonas Skovgaard-Petersen, Andreas Jurik, Stine B. Vogensen, Gerhard Ecker, Arne Schousboe, Povl Krogsgaard-Larsen, and Rasmus P. Clausen    4.1 Introduction 69    4.2 GABA Transporters 73    4.3 Glycine Transporters 90    4.4 Conclusions and Future Perspectives 95    References 96    5 ABC Transporters: From Targets to Antitargets and Back 107 Gerhard F. Ecker    5.1 Introduction 107    5.2 ABC Transporter as Drug Targets 109    5.3 ABC Transporter: from Targets to Antitargets 111    5.4 Pharmacochaperones and Beyond 113    5.5 Conclusions and Outlook 114    Acknowledgment 115    References 115    6 ABC Transporters Involved in Cholestasis 119 Frans J. C. Cuperus, Julien Gautherot, Emina Halilbasic, Thierry Claudel, and Michael Trauner    6.1 Introduction 119    6.2 Canalicular ABC Transporters 122    6.3 Basolateral ABC Transporters 136    6.4 Nuclear Receptors as Drug Targets 140    6.5 Ursodeoxycholic Acid Treatment in Cholestatic Liver Disease 144    6.6 Conclusions 145    References 145    7 Recent Advances in Structural Modeling of ABC Transporters 167 Dennis Haake, Peter Chiba, and Gerhard F. Ecker    7.1 Introduction 167    7.2 ABC Transporter Modeling Attempts Since 2001 168    7.3 Retraction of Five Transporter Structures 170    7.4 First Mammalian ABC Transporter Structure 173    7.5 Conclusions and Perspectives 175    Acknowledgment 175    References 175    8 PET Imaging of ABC Transporters at the Blood   Brain Barrier 179 Oliver Langer    8.1 The Blood   Brain Barrier 179    8.2 The Brain as a Pharmacological Sanctuary 180    8.3 Implication of ABC Transporters in Neurological Disorders 180    8.4 Positron Emission Tomography 181    8.5 PET Imaging of ABC Transporters 181    8.6 Challenges in Designing PET Tracers for ABC Transporters 184    8.7 Potential Applications of PET Tracers for ABC Transporters 184    8.8 Overview of Available PET Tracers for Cerebral ABC Transporters 185    8.9 Summary 191    Abbreviations 191    References 191    9 The Systems Biology of Transporters     Targeting the Regulatory System for Transporters (FXR/RXR) 199 Antimo Gioiello, Maura Marinozzi, Bruno Cerra, Chiara Custodi, Roberto Pellicciari, and Antonio Macchiarulo    9.1 Introduction 199    9.2 Discovery and Pharmacological Characterization of FXR 200    9.3 Regulation of the Hepatobiliary Transport System by FXR 201    9.4 Genetic and Structural Properties of FXR 207    9.5 FXR Ligands 209    9.6 Conclusions and Perspectives 221    References 221    10 ANO1 as a Novel Drug Target 231 Anke Bill and Larry Alex Gaither    10.1 Introduction 231    10.2 ANO1: a Calcium Activated Chloride Channel 232    10.3 Pharmacological Targeting of ANO1 238    10.4 ANO1 as a Therapeutic Target 241    10.5 Concluding Remarks 246    References 247    11 Ligand Discovery for the Nutrient Transporters ASCT2 and LAT-1 from Homology Modeling and Virtual Screening 253 Claire Colas and Avner Schlessinger    11.1 Solute Carriers in Cancer Metabolism 253    11.2 In Silico Methods for Structure-based Drug Design 255    11.3 Emerging Cancer Metabolism Targets 260    11.4 Conclusions and Future Outlook 263    Acknowledgment 265    References 265    12 Organic Anion Transporting Polypeptides as Drug Targets 271 Eleni Kotsampasakou and Gerhard F. Ecker    12.1 Introduction 271    12.2 OATPs and Genetic Diseases 285    12.3 OATPs and Cancer 286    12.4 OATPs as Diagnostic Markers 301    12.5 OATPs and Selective Delivery of Drugs 301    12.6 Potential Protective Role of OATPs 309    12.7 OATPs and Drug   Drug Interactions 311    12.8 Conclusions and Outlook 312    Acknowledgments 313    Abbreviation List 313    References 314    Index 325