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A Pharmacology Primer
Techniques for More Effective and Strategic Drug Discovery
4th Edition - March 26, 2014
Author: Terry P. Kenakin
Language: English
Hardback ISBN:9780124076631
9 7 8 - 0 - 1 2 - 4 0 7 6 6 3 - 1
eBook ISBN:9780124076891
9 7 8 - 0 - 1 2 - 4 0 7 6 8 9 - 1
A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, 4th Edition features the latest ideas and research about the application of pharmacology to the…Read more
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A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, 4th Edition features the latest ideas and research about the application of pharmacology to the process of drug discovery to equip readers with a deeper understanding of the complex and rapid changes in this field. Written by well-respected pharmacologist, Terry P. Kenakin, this primer is an indispensable resource for all those involved in drug discovery. This edition has been thoroughly revised to include material on data-driven drug discovery, biased signaling, structure-based drug design, drug activity screening, drug development (including pharmacokinetics and safety Pharmacology), and much more. With more color illustrations, examples, and exercises throughout, this book remains a top reference for all industry and academic scientists and students directly involved in drug discovery, or pharmacologic research.
Highlights changes surrounding the strategy of drug discovery to provide you with a comprehensive reference featuring advances in the methods involved in lead optimization and more effective drug discovery
Includes a new chapter on data-driven drug discovery in terms of the optimal design of pharmacological experiments to identify mechanism of action of new molecules
Illustrates the application of rapid inexpensive assays to predict activity in the therapeutic setting, showing data outcomes and the limitations inherent in interpreting this data
Industry, academic and regulatory scientists involved in drug discovery or pharmacologic research, medicinal chemists and industrial chemists; graduate and post-doctoral students in pharmacology and pharmaceutical science programs
Dedication
Preface
Preface. Preface to the Third Edition
Preface. Preface to the Second Edition
Preface. Preface to the First Edition
Chapter 1. What Is Pharmacology?
1.1 About This Book
1.2 What Is Pharmacology?
1.3 The Receptor Concept
1.4 Pharmacological Test Systems
1.5 The Nature of Drug Receptors
1.6 Pharmacological Intervention and the Therapeutic Landscape
1.7 System-Independent Drug Parameters: Affinity and Efficacy
1.8 What is Affinity?
1.9 The Langmuir Adsorption Isotherm
1.10 What is Efficacy?
1.11 Dose-Response Curves
1.12 Chapter Summary and Conclusions
1.13 Derivations: Conformational Selection as a Mechanism of Efficacy
References
Chapter 2. How Different Tissues Process Drug Response
2.1 Drug Response as Seen Through the “Cellular Veil”
2.2 The Biochemical Nature of Stimulus-Response Cascades
2.3 The Mathematical Approximation of Stimulus-Response Mechanisms
2.4 System Effects On Agonist Response: Full and Partial Agonists
2.5 Differential Cellular Response to Receptor Stimulus
2.6 Receptor Desensitization and Tachyphylaxis
2.7 The Measurement of Drug Activity
2.8 Advantages and Disadvantages of Different Assay Formats
2.9 Drug Concentration as an Independent Variable
2.10 Chapter Summary and Conclusions
2.11 Derivations
References
Chapter 3. Drug-Receptor Theory
3.1 About This Chapter
3.2 Drug-Receptor Theory
3.3 The Use of Mathematical Models in Pharmacology
3.4 Some Specific Uses of Models in Pharmacology
3.5 Classical Model of Receptor Function
3.6 The Operational Model of Receptor Function
3.7 Two-State Theory
3.8 The Ternary Complex Model
3.9 The Extended Ternary Complex Model
3.10 Constitutive Receptor Activity and Inverse Agonism
3.11 The Cubic Ternary Complex Model
3.12 Multistate Receptor Models and Probabilistic Theory
3.13 Chapter Summary and Conclusions
3.14 Derivations
References
Chapter 4. Pharmacological Assay Formats: Binding
4.1 The Structure of This Chapter
4.2 Binding Theory and Experiment
4.3 Complex Binding Phenomena: Agonist Affinity from Binding Curves
4.4 Experimental Prerequisites for Correct Application of Binding Techniques
4.5 Chapter Summary and Conclusions
4.6 Derivations
References
Chapter 5. Agonists: The Measurement of Affinity and Efficacy in Functional Assays
5.1 Functional Pharmacological Experiments
5.2 The Choice of Functional Assays
5.3 Recombinant Functional Systems
5.4 Functional Experiments: Dissimulation in Time
5.5 Experiments in Real Time Versus Stop-Time
5.6 Quantifying Agonism: The Black-Leff Operational Model of Agonism
5.7 Biased Signaling
5.8 Null Analyses of Agonism
5.9 Chapter Summary and Conclusions
5.10 Derivations
References
Chapter 6. Orthosteric Drug Antagonism
6.1 Introduction
6.2 Kinetics of Drug-Receptor Interaction
6.3 Surmountable Competitive Antagonism
6.4 Noncompetitive Antagonism
6.5 Agonist-Antagonist Hemi-Equilibria
6.6 Resultant Analysis
6.7 Antagonist Receptor Coverage: Kinetics of Dissociation
6.8 Blockade of Indirectly Acting Agonists
6.9 Irreversible Antagonism
6.10 Chemical Antagonism
6.11 Chapter Summary and Conclusions
6.12 Derivations
References
Chapter 7. Allosteric Modulation
7.1 Introduction
7.2 The Nature of Receptor Allosterism
7.3 Unique Effects of Allosteric Modulators
7.4 Functional Study of Allosteric Modulators
7.5 Methods for Detecting Allosterism
7.6 Chapter Summary and Conclusions
7.7 Derivations
References
Chapter 8. The Optimal Design of Pharmacological Experiments
8.1 Introduction
8.2 The Optimal Design of Pharmacological Experiments
8.3 Null Experiments and Fitting Data to Models
8.4 Interpretation of Experimental Data
8.5 Predicting Therapeutic Activity in All Systems
8.6 Summary and Conclusions
8.7 Derivations
References
Chapter 9. Pharmacokinetics
9.1 Introduction
9.2 Biopharmaceutics
9.3 The Chemistry of “Druglike” Character
9.4 Pharmacokinetics
9.5 Nonlinear Pharmacokinetics
9.6 Multiple Dosing
9.7 Practical Pharmacokinetics
9.8 Placement of Pharmacokinetic Assays in Discovery and Development
9.9 Summary and Conclusions
References
Chapter 10. Safety Pharmacology
10.1 Safety Pharmacology
10.2 Hepatotoxicity
10.3 Cytotoxicity
10.4 Mutagenicity
10.5 hERG Activity and Torsades De Pointes
10.6 Autonomic Receptor Profiling
10.7 General Pharmacology
10.8 Clinical Testing
10.9 Summary and Conclusions
References
Chapter 11. The Drug Discovery Process
11.1 Some Challenges for Modern Drug Discovery
11.2 Target-Based Drug Discovery
11.3 Systems-Based Drug Discovery
11.4 In vivo Systems, Biomarkers, and Clinical Feedback
11.5 Types of Therapeutically Active Ligands: Polypharmacology
11.6 Pharmacology in Drug Discovery
11.7 Chemical Sources for Potential Drugs
11.8 Pharmacodynamics and High-Throughput Screening
11.9 Drug Development
11.10 Clinical Testing
11.11 Summary and Conclusions
References
Chapter 12. Statistics and Experimental Design
12.1 Structure of This Chapter
12.2 Introduction
12.3 Descriptive Statistics: Comparing Sample Data
12.4 How Consistent is Experimental Data with Models?
12.5 Comparison of Samples to “Standard Values”
12.6 Experimental Design and Quality Control
12.7 Chapter Summary and Conclusions
References
Chapter 13. Selected Pharmacological Methods
13.1 Binding Experiments
13.2 Functional Assays
Chapter 14. Exercises in Pharmacodynamics and Pharmacokinetics
14.1 Introduction
14.2 Agonism
14.3 Antagonism
14.4 In vitro–In vivo Transitions and General Discovery
14.5 SAR Exercises
14.6 Pharmacokinetics
14.7 Conclusions
References
Appendices
A.1 Statistical Tables of Use for Assessing Significant Difference
A.2 Mathematical Fitting Functions
Glossary. Glossary of Pharmacological Terms
Index
No. of pages: 450
Language: English
Edition: 4
Published: March 26, 2014
Imprint: Academic Press
Hardback ISBN: 9780124076631
eBook ISBN: 9780124076891
TK
Terry P. Kenakin
Dr. Terry Kenakin is Professor of Pharmacology at the University of North Carolina School of Medicine. Prior to this, he spent 7 years in drug discovery at Burroughs-Wellcome. He then moved to GlaxoSmithKline for 25 years. Dr. Kenakin has written 11 books on Pharmacology, is the Editor in Chief of the Journal of Receptors and Signal Transduction, is on numerous Editorial Boards. He is the Editor-in-Chief of Comprehensive Pharmacology (Elsevier, 2022). He is the recipient of the 2008 Poulsson Medal for Pharmacology awarded by the Norwegian Society of Pharmacology for achievements in basic and clinical pharmacology and toxicology. He has also been awarded the 2011 Ariens Award from the Dutch Pharmacological Society and the 2014 Gaddum Memorial Award from the British Pharmacological Society, and the 2020 Goodman and Gilman Award in Receptor Pharmacology from ASPET.
Affiliations and expertise
Professor, Pharmacology, University of North Carolina, USA