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Molecular Pharmacology: From DNA to Drug Design

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This textbook provides a fresh, comprehensive and accessible introduction to the rapidly expanding field of molecular pharmacology. Adopting a drug target-based, rather than the traditional organ/system based, approach this innovative guide reflects the current advances and research trend towards molecular based drug design, derived from a detailed understanding of chemical responses in the body. Drugs are then tailored to fit a treatment profile, rather than the traditional method of ‘trial and error’ drug ...

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Overview

This textbook provides a fresh, comprehensive and accessible introduction to the rapidly expanding field of molecular pharmacology. Adopting a drug target-based, rather than the traditional organ/system based, approach this innovative guide reflects the current advances and research trend towards molecular based drug design, derived from a detailed understanding of chemical responses in the body. Drugs are then tailored to fit a treatment profile, rather than the traditional method of ‘trial and error’ drug discovery which focuses on testing chemicals on animals or cell cultures and matching their effects to treatments.

Providing an invaluable resource for advanced under-graduate and MSc/PhD students, new researchers to the field and practitioners for continuing professional development, Molecular Pharmacology explores; recent advances and developments in the four major human drug target families (G-protein coupled receptors, ion channels, nuclear receptors and transporters), cloning of drug targets, transgenic animal technology, gene therapy, pharmacogenomics and looks at the role of calcium in the cell.

  • Current - focuses on cutting edge techniques and approaches, including new methods to quantify biological activities in different systems and ways to interpret and understand pharmacological data.
  • Cutting Edge - highlights advances in pharmacogenomics and explores how an individual’s genetic makeup influences their response to therapeutic drugs and the potential for harmful side effects.
  • Applied - includes numerous, real-world examples and a detailed case-study based chapter which looks at current and possible future treatment strategies for cystic fibrosis. This case study considers the relative merits of both drug therapy for specific classes of mutation and gene therapy to correct the underlying defect.
  • Accessible - contains a comprehensive glossary, suggestions for further reading at the end of each chapter and an associated website that provides a complete set of figures from within the book.

A companion website with additional resources is available at www.wiley.com/go/dickenson/dnamolecular

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Editorial Reviews

From the Publisher
“Overall, it could be the basis of an excellent course for junior pharmacologists in basic science research who need a greater focus on the mechanisms of drug action rather than an encyclopedic survey of clinical drug use.” (Doody’s, 26 July 2013)
Doody's Review Service
Reviewer: Kenneth E. McCarson, BChE, PhD (University of Kansas Medical Center)
Description: This book provides a platform for teaching the fundamental aspects of molecular pharmacology from a fresh perspective that emphasizes genes, targets, and drug-design approaches that drive modern pharmacology research rather than the typical organ- or disease-based survey strategy employed by most basic graduate pharmacology books. An introductory chapter clearly plots the intent of the text, and the 11 remaining chapters describe the major target classes and mediators important in pharmacological responses. Chapters on pharmacogenomics, genetic model engineering, and a genetic disease example strengthen the impact of the book considerably.
Purpose: The editors and authors, a team from Nottingham Trent University in the U.K., unfortunately state their primary goal is to complement their students' course experiences, outcomes of which are difficult to infer. However, the authors have devised a clearly organized source for postgraduate pharmacology students to find detailed information on a broad set of highly relevant gene products and the currently favored approaches for researching their function and targeting them with new drugs. This approach provides welcome relief from the typical systems-based survey of pharmacology that better suits students headed toward clinical careers. In this regard, the book provides a very strong bridge between basic physiology and biochemistry or introductory general pharmacological principles and general broad pharmacology and therapeutics courses.
Audience: As is the intent of the editors, this book is appropriate for postgraduate pharmacology or neuropharmacology trainees. Readers certainly need a relatively high undergraduate level understanding of physiology and biochemistry to benefit from this book. The breadth of topics and targets addressed, combined with the depth of detail in each chapter would also, as the editors suggest, make the book useful to postgraduate researchers as a reference source. The editors and authors are established researchers in the bioscience department at Nottingham Trent and bring considerable expertise to the task.
Features: This book provides a solid body of detailed information about the molecular targets and mechanisms that underlie most of the relevant targets for drug development in modern pharmacology research. An introductory chapter sets the stage by defining a perspective that emphasizes the importance of the targets and approaches described in the chapters on current drug development strategies. Chapters then provide in-depth discussions of the major classes of drug targets, including GPCRs, ion channels, transporters, and nuclear receptors. Others address major mechanisms that regulate intracellular signaling, such as calcium and protein interactions. The book is especially good at incorporating issues related to genetics, such as pharmacogenomics and engineering of mutant models of disease. One chapter provides an example of how each of these approaches and several targets are involved in a specific disease (cystic fibrosis). The level of the material is very even across all chapters, and there is little or no redundancy or overlap between them. The supporting graphics are outstanding in both content and visual quality. A useful glossary is included, as is an index.
Assessment: This is successful as a complete, well-integrated overview of the major current topics in molecular pharmacology. The breadth of subjects addressed is wide and comprehensive enough to support a complete introductory course on this material, but also provides excellent depth and detail in each chapter. This book has more even coverage of this large field without the gaps in topics evident in other mechanism-based molecular pharmacology books. Overall, it could be the basis of an excellent course for junior pharmacologists in basic science research who need a greater focus on the mechanisms of drug action rather than an encyclopedic survey of clinical drug use.
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Product Details

  • ISBN-13: 9780470684436
  • Publisher: Wiley
  • Publication date: 1/22/2013
  • Edition number: 1
  • Pages: 424
  • Product dimensions: 7.40 (w) x 9.60 (h) x 0.80 (d)

Table of Contents

Preface ix

Abbreviations x

1 Introduction to Drug Targets and Molecular Pharmacology 1

1.1 Introduction to molecular pharmacology 1

1.2 Scope of this textbook 2

1.3 The nature of drug targets 3

1.4 Future drug targets 7

1.5 Molecular pharmacology and drug discovery 11

References 12

2 Molecular Cloning of Drug Targets 13

2.1 Introduction to molecular cloning – from DNA to drug discovery 13

2.2 ‘Traditional’ pharmacology 14

2.3 The relevance of recombinant DNA technology to pharmacology/drug

discovery 14

2.4 The ‘cloning’ of drug targets 15

2.5 What information can DNA cloning provide? 20

2.6 Comparing the pharmacologic profile of the ‘cloned’ and the ‘native’

drug target 23

2.7 Reverse pharmacology illustrated on orphan GPCRs 24

2.8 Summary 27

References 27

3 G Protein-coupled Receptors 31

3.1 Introduction to G protein-coupled receptors 31

3.2 Heterotrimeric G-proteins 36

3.3 Signal transduction pathways 40

3.4 Desensitisation and down-regulation of GPCR signalling 44

3.5 Constitutive GPCR activity 45

3.6 Promiscuous G-protein coupling 47

3.7 Agonist-directed signalling 48

3.8 Allosteric modulators of GPCR function 49

3.9 Pharmacological chaperones for GPCRs 50

3.10 GPCR dimerisation 51

3.11 GPCR splice variants 63

3.12 Summary 67

References 67

Useful Web sites 70

4 Ion Channels 71

4.1 Introduction 71

4.2 Voltage-gated ion channels 73

4.3 Other types of voltage-gated ion channels 89

4.4 Ligand-gated ion channels 109

4.5 Summary 125

References 125

5 Transporter Proteins 129

5.1 Introduction 129

5.2 Classification 129

5.3 Structural analysis of transporters 132

5.4 Transporter families of pharmacological interest 133

5.5 Transporters and cellular homeostasis 167

5.6 Summary 169

References 169

6 Cystic Fibrosis: Alternative Approaches to the Treatment of a Genetic Disease 175

6.1 Introduction 175

6.2 Cystic fibrosis transmembrane conductance regulator 179

6.3 Mutations in CFTR 183

6.4 Why is cystic fibrosis so common? 184

6.5 Animal models of Cystic fibrosis 186

6.6 Pharmacotherapy 186

6.7 Gene therapy 191

6.8 Conclusion 195

References 196

7 Pharmacogenomics 201

7.1 Types of genetic variation in the human genome 201

7.2 Thiopurine S-methyltransferase and K+ channel polymorphisms 202

7.3 Polymorphisms affecting drug metabolism 204

7.4 Methods for detecting genetic polymorphisms 209

7.5 Genetic variation in drug transporters 211

7.6 Genetic variation in G protein coupled receptors 215

7.7 Summary 225

References 225

Useful Web sites 226

8 Transcription Factors and Gene Expression 227

8.1 Control of gene expression 227

8.2 Transcription factors 229

8.3 CREB 233

8.4 Nuclear receptors 238

8.5 Peroxisome proliferator-activated receptors 240

8.6 Growth factors 247

8.7 Alternative splicing 247

8.8 RNA editing 251

8.9 The importance of non-coding RNAs in gene expression 257

8.10 Summary 270

References 271

9 Cellular Calcium 277

9.1 Introduction 277

9.2 Measurement of calcium 278

9.3 The exocrine pancreas 289

9.4 Calcium signalling in pancreatic acinar cells 292

9.5 Nuclear calcium signalling 303

9.6 Conclusions 310

References 311

10 Genetic Engineering of Mice 315

10.1 Introduction to genetic engineering 315

10.2 Genomics and the accumulation of sequence data 315

10.3 The mouse as a model organism 318

10.4 Techniques for genetic engineering 319

10.5 Examples of genetically-engineered mice 332

10.6 Summary 334

References 334

11 Signalling Complexes: Protein-protein Interactions and Lipid Rafts 339

11.1 Introduction to cell signalling complexes 339

11.2 Introduction to GPCR interacting proteins 340

11.3 Methods used to identify GPCR interacting proteins 340

11.4 Functional roles of GPCR interacting proteins 345

11.5 GPCR signalling complexes 348

11.6 GPCR and ion channel complexes 355

11.7 Ion channel signalling complexes 356

11.8 Development of pharmaceuticals that target GPCR interacting proteins 356

11.9 Development of pharmaceuticals that target protein-protein interactions 356

11.10 Lipid rafts 357

11.11 Receptor-mediated endocytosis 361

11.12 Summary 364

References 364

12 Recombinant Proteins and Immunotherapeutics 367

12.1 Introduction to immunotherapeutics 367

12.2 Historical background of immunotherapeutics 368

12.3 Basis of immunotherapeutics 368

12.4 Types of immunotherapeutics 369

12.5 Humanisation of antibody therapy 372

12.6 Immunotherapeutics in clinical practice 376

12.7 Advantages and disadvantages of immunotherapy 378

12.8 The future 379

12.9 Summary 380

References 380

Glossary 381

Index 403

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