Transporters as Targets for Drugs (eBook)

Volume Editors 5
Editorial Board 5
Topics in Medicinal Chemistry Also Available Electronically 6
Preface to the Series 7
Preface to Volume 4 8
Contents 9
Overview: Transporters as Targets for Drug Discovery 10
1 Introduction 11
2 Transporter Classification 11
3 NSS Transporter Assays 14
4 Transporters and Structure-Based Drug Design (SBDD) 15
5 Transporters as Targets for Drug Discovery 17
6 Summary 20
References 20
Membrane Transporters: Structure, Function and Targets for Drug Design 23
1 Introduction 25
2 Membrane Protein Structures 27
3 Membrane Transporter Proteins 28
4 Structure Determination of Membrane Proteins 32
5 Transporters of Known 3D Structure 37
6 Potential for New Drug Development 44
7 Conclusions 54
References 55
Design of Monoamine Reuptake Inhibitors: SSRIs, SNRIs and NRIs 60
1 Introduction 61
2 Selective Serotonin Reuptake Inhibitors 64
3 Dual Serotonin and Noradrenaline Reuptake Inhibitors 72
4 Noradrenaline Reuptake Inhibitors 87
5 Conclusions 98
References 98
Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine’s Mechanism at the Dopamine Transporter 102
1 Introduction –Chemical and Pharmacological Diversity of Dopamine Uptake Inhibitors 103
2 Case Study: Benztropine Analogues 104
3 Design, Synthesis and SAR of the Benztropine Analogues 106
4 In Vivo Findings 116
5 Mechanisms for Differences with Cocaine 121
6 Preclinical Assessment of Cocaine-Abuse Therapy 130
7 Summary and Conclusions 133
References 134
The Design, Synthesis and Structure–Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors 137
1 Introduction 138
2 Overview of Dual-Uptake Inhibitors 140
3 Design, Synthesis and Structure– Activity Relationship of Triple- Uptake Inhibitors 143
4 Conclusions 157
References 158
Molecular Imaging of Transporters with Positron Emission Tomography 161
1 Introduction 163
2 PET Principles 164
3 PET Studies of Transporters 170
4 Conclusions 186
References 187
Pharmacology of Glutamate Transport in the CNS:Substrates and Inhibitorsof Excitatory Amino Acid Transporters (EAATs)and the Glutamate/Cystine Exchanger System x–c 193
1 Introduction 195
2 Excitatory Amino Acid Transporters (EAATs) 196
3 System x–c : Cystine/Glutamate Exchanger 214
References 223
Glycine Transporters and Their Inhibitors 229
1 Introduction 230
2 Glycine Transporter Isoforms 230
3 Distribution 231
4 Function 232
5 Therapeutic Potential 233
6 Medicinal Chemistry of Glycine Transporter Inhibitors 235
7 Conclusion 247
References 247
Subject Index 254