A Pharmacology Primer
Techniques for More Effective and Strategic Drug Discovery
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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.
Key Features
- 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
Readership
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
Table of Contents
- 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
Product details
- No. of pages: 450
- Language: English
- Copyright: © Academic Press 2014
- Published: March 26, 2014
- Imprint: Academic Press
- eBook ISBN: 9780124076891
- Hardcover ISBN: 9780124076631
About the Author
Terry 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