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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 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

Molecular Pharmacology: From DNA to Drug Design

Preface ixAbbreviations x1 Introduction to Drug Targets and Molecular Pharmacology 11.1 Introduction to molecular pharmacology 11.2 Scope of this textbook 21.3 The nature of drug targets 31.4 Future drug targets 71.5 Molecular pharmacology and drug discovery 11References 122 Molecular Cloning of Drug Targets 132.1 Introduction to molecular cloning - from DNA to drug discovery 132.2 'Traditional' pharmacology 142.3 The relevance of recombinant DNA technology to pharmacology/drug discovery 142.4 The 'cloning' of drug targets 152.5 What information can DNA cloning provide? 202.6 Comparing the pharmacologic profile of the 'cloned' and the 'native' drug target 232.7 Reverse pharmacology illustrated on orphan GPCRs 242.8 Summary 27References 273 G Protein-coupled Receptors 313.1 Introduction to G protein-coupled receptors 313.2 Heterotrimeric G-proteins 363.3 Signal transduction pathways 403.4 Desensitisation and down-regulation of GPCR signalling 443.5 Constitutive GPCR activity 453.6 Promiscuous G-protein coupling 473.7 Agonist-directed signalling 483.8 Allosteric modulators of GPCR function 493.9 Pharmacological chaperones for GPCRs 503.10 GPCR dimerisation 513.11 GPCR splice variants 633.12 Summary 67References 67Useful Web sites 704 Ion Channels 714.1 Introduction 714.2 Voltage-gated ion channels 734.3 Other types of voltage-gated ion channels 894.4 Ligand-gated ion channels 1094.5 Summary 125References 1255 Transporter Proteins 1295.1 Introduction 1295.2 Classification 1295.3 Structural analysis of transporters 1325.4 Transporter families of pharmacological interest 1335.5 Transporters and cellular homeostasis 1675.6 Summary 169References 1696 Cystic Fibrosis: Alternative Approaches to the Treatment of a Genetic Disease 1756.1 Introduction 1756.2 Cystic fibrosis transmembrane conductance regulator 1796.3 Mutations in CFTR 1836.4 Why is cystic fibrosis so common? 1846.5 Animal models of Cystic fibrosis 1866.6 Pharmacotherapy 1866.7 Gene therapy 1916.8 Conclusion 195References 1967 Pharmacogenomics 2017.1 Types of genetic variation in the human genome 2017.2 Thiopurine S-methyltransferase and K+ channel polymorphisms 2027.3 Polymorphisms affecting drug metabolism 2047.4 Methods for detecting genetic polymorphisms 2097.5 Genetic variation in drug transporters 2117.6 Genetic variation in G protein coupled receptors 2157.7 Summary 225References 225Useful Web sites 2268 Transcription Factors and Gene Expression 2278.1 Control of gene expression 2278.2 Transcription factors 2298.3 CREB 2338.4 Nuclear receptors 2388.5 Peroxisome proliferator-activated receptors 2408.6 Growth factors 2478.7 Alternative splicing 2478.8 RNA editing 2518.9 The importance of non-coding RNAs in gene expression 2578.10 Summary 270References 2719 Cellular Calcium 2779.1 Introduction 2779.2 Measurement of calcium 2789.3 The exocrine pancreas 2899.4 Calcium signalling in pancreatic acinar cells 2929.5 Nuclear calcium signalling 3039.6 Conclusions 310References 31110 Genetic Engineering of Mice 31510.1 Introduction to genetic engineering 31510.2 Genomics and the accumulation of sequence data 31510.3 The mouse as a model organism 31810.4 Techniques for genetic engineering 31910.5 Examples of genetically-engineered mice 33210.6 Summary 334References 33411 Signalling Complexes: Protein-protein Interactions and Lipid Rafts 33911.1 Introduction to cell signalling complexes 33911.2 Introduction to GPCR interacting proteins 34011.3 Methods used to identify GPCR interacting proteins 34011.4 Functional roles of GPCR interacting proteins 34511.5 GPCR signalling complexes 34811.6 GPCR and ion channel complexes 35511.7 Ion channel signalling complexes 35611.8 Development of pharmaceuticals that target GPCR interacting proteins 35611.9 Development of pharmaceuticals that target protein-protein interactions 35611.10 Lipid rafts 35711.11 Receptor-mediated endocytosis 36111.12 Summary 364References 36412 Recombinant Proteins and Immunotherapeutics 36712.1 Introduction to immunotherapeutics 36712.2 Historical background of immunotherapeutics 36812.3 Basis of immunotherapeutics 36812.4 Types of immunotherapeutics 36912.5 Humanisation of antibody therapy 37212.6 Immunotherapeutics in clinical practice 37612.7 Advantages and disadvantages of immunotherapy 37812.8 The future 37912.9 Summary 380References 380Glossary 381Index 403