A Pharmacology Primer

Techniques for More Effective and Strategic Drug Discovery

6th Edition - August 14, 2022

Author: Terry P. Kenakin

Paperback ISBN:

9 7 8 - 0 - 3 2 3 - 9 9 2 8 9 - 3

eBook ISBN:

9 7 8 - 0 - 3 2 3 - 9 9 2 9 0 - 9

A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, Sixth Edition features the latest research surrounding the application of pharmacology in drug… Read more

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A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, Sixth Edition features the latest research surrounding the application of pharmacology in drug discovery in an effort to equip readers with a deeper understanding of complex and rapid changes in this field. Written by well-respected pharmacologist, Terry P. Kenakin, this primer is an indispensable resource for anyone involved in drug discovery. This edition has been reorganized for better flow and clarity and includes material on new technologies for screening (virtual, DNA encoded libraires, fragment-based) and a major section on phenotypic (target agnostic) screening for new leads and determination of drug targets.

With full color illustrations as well as new examples throughout, this book remains a top reference for all industry and academic scientists and students directly involved in drug discovery or pharmacologic research. New material includes a discussion of the determination of target engagement, including numerous new ways to demonstrate the physical interaction of molecules with drug targets and new drug candidates such a mRNA, gene therapy, antibodies and information on CRISPR and genomics.

Cover image
Title page
Table of Contents
HTU
Copyright
Dedication
Preface to sixth 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. From the snapshot to the movie
1.7. Pharmacological intervention and the therapeutic landscape
1.8. System-independent drug parameters: affinity and efficacy
1.9. What is affinity?
1.10. The Langmuir adsorption isotherm
1.11. What is efficacy?
1.12. Dose–response curves
1.13. Chapter summary and conclusions
1.14. Derivations: conformational selection as a mechanism of efficacy
Chapter 2. How different tissues process drug response
2.1. The ‘eyes to see’: pharmacologic assays
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
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. Mass action building blocks
3.6. Classical model of receptor function
3.7. The operational model of receptor function
3.8. Two-state theory
3.9. The ternary complex model
3.10. The extended ternary complex model
3.11. Constitutive receptor activity and inverse agonism
3.12. The cubic ternary complex model
3.13. Multistate receptor models and probabilistic theory
3.14. Chapter summary and conclusions
3.15. Derivations
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. Binding in allosteric systems
4.6. Chapter summary and conclusions
4.7. Derivations
Chapter 5. Drug targets and drug-target molecules
5.1. Defining biological targets
5.2. Specific types of drug targets
5.3. Small drug-like molecules
5.4. Biologics
5.5. Summary and conclusions
Chapter 6. Agonists: the measurement of affinity and efficacy in functional assays
6.1. Functional pharmacological experiments
6.2. The choice of functional assays
6.3. Recombinant functional systems
6.4. Functional experiments: dissimulation in time
6.5. Experiments in real time versus stop-time
6.6. Quantifying agonism: the Black–Leff operational model of agonism
6.7. Biased signaling
6.8. Null analyses of agonism
6.9. Comparing full and partial agonist activities: Log(max/EC50)
6.10. Chapter summary and conclusions
6.11. Derivations
Chapter 7. Orthosteric drug antagonism
7.1. Introduction
7.2. Kinetics of drug–receptor interaction
7.3. Surmountable competitive antagonism
7.4. Noncompetitive antagonism
7.5. Agonist–antagonist hemiequilibria
7.6. Resultant analysis
7.7. Antagonism in vivo
7.8. Blockade of indirectly acting agonists
7.9. Irreversible antagonism
7.10. Chemical antagonism
7.11. Chapter summary and conclusions
7.12. Derivations
Chapter 8. Allosteric modulation
8.1. Introduction
8.2. The nature of receptor allosterism
8.3. Unique effects of allosteric modulators
8.4. Functional study of allosteric modulators
8.5. Functional allosteric model with constitutive activity
8.6. Internal checks for adherence to the allosteric model
8.7. Methods for detecting allosterism
8.8. Chapter summary and conclusions
8.9. Derivations
Chapter 9. The optimal design of pharmacological experiments
9.1. Introduction
9.2. The optimal design of pharmacological experiments
9.3. Null experiments and fitting data to models
9.4. Interpretation of experimental data
9.5. Predicting therapeutic activity in all systems
9.6. Summary and conclusions
9.7. Derivations
Chapter 10. Pharmacokinetics
10.1. Introduction
10.2. Biopharmaceutics
10.3. The chemistry of “drug-like” character
10.4. Pharmacokinetics
10.5. Nonlinear pharmacokinetics
10.6. Multiple dosing
10.7. Modifying pharmacokinetics through medicinal chemistry
10.8. Practical pharmacokinetics
10.9. Placement of pharmacokinetic assays in discovery and development
10.10. The pharmacokinetics of biologics
10.11. Summary and conclusions
Chapter 11. Safety pharmacology
11.1. Safety pharmacology
11.2. Hepatotoxicity
11.3. Cytotoxicity
11.4. Mutagenicity
11.5. hERG activity and Torsades de Pointes
11.6. Autonomic receptor profiling and off-target effects
11.7. General pharmacology
11.8. Clinical testing and drug toxicity
11.9. Summary and conclusions
Chapter 12. The drug-discovery process
12.1. Some challenges for modern drug discovery
12.2. The drug-discovery process
12.3. Target-based drug discovery
12.4. Systems-based drug discovery
12.5. High-throughput screening
12.6. The lead optimization process
12.7. Drug effectiveness
12.8. Summary and conclusions
Chapter 13. Selected pharmacological methods
13.1. Binding experiments
13.2. Functional assays
Appendix 1. Statistics
Index