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A Pharmacology Primer
Techniques for More Effective and
Strategic Drug Discovery
FIFTH EDITION
Terry P. Kenakin, PhD
Professor, Department of Pharmacology, University of North Carolina
School of Medicine, United States
Table of Contents
Title page
Copyright
Dedication
Preface
Chapter 1. What is Pharmacology?
Abstract
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
Abstract
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 Influence of Stimulus–Response Cascades on Dose–
Response Curve Slopes
2.5 System Effects on Agonist Response: Full and Partial
Agonists
2.6 Differential Cellular Response to Receptor Stimulus
2.7 Receptor Desensitization and Tachyphylaxis
2.8 The Measurement of Drug Activity
2.9 Advantages and Disadvantages of Different Assay Formats
2.10 Drug Concentration as an Independent Variable
2.11 Chapter Summary and Conclusions
2.12 Derivations
References
Further Reading
Chapter 3. Drug–Receptor Theory
Abstract
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
Abstract
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 Binding in Allosteric Systems
4.6 Chapter Summary and Conclusions
4.7 Derivations
References
Chapter 5. Agonists: The Measurement of Affinity and Efficacy in
Functional Assays
Abstract
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 Comparing Full and Partial Agonist Activities: Log(max/EC50)
5.10 Chapter Summary and Conclusions
5.11 Derivations
References
Chapter 6. Orthosteric Drug Antagonism
Abstract
6.1 Introduction
6.2 Kinetics of Drug–Receptor Interaction
6.3 Surmountable Competitive Antagonism
6.4 Noncompetitive Antagonism
6.5 Agonist–Antagonist Hemiequilibria
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
Abstract
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
Abstract
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
Further Reading
Chapter 9. Pharmacokinetics
Abstract
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 Modifying Pharmacokinetics Through Medicinal Chemistry
9.8 Practical Pharmacokinetics
9.9 Placement of Pharmacokinetic Assays in Discovery and
Development
9.10 Summary and Conclusions
References
Chapter 10. Safety Pharmacology
Abstract
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 and Off-Target Effects
10.7 General Pharmacology
10.8 Clinical Testing and Drug Toxicity
10.9 Summary and Conclusions
References
Chapter 11. The Drug Discovery Process
Abstract
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 Clinical Testing
11.10 Summary and Conclusions
References
Chapter 12. Statistics and Experimental Design
Abstract
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
Abstract
13.1 Binding Experiments
13.2 Functional Assays
Reference
Chapter 14. Exercises in Pharmacodynamics and Pharmacokinetics
Abstract
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
Index
Copyright
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