Pharmacology in Drug Discovery and Development

Pharmacology in Drug Discovery and Development

Understanding Drug Response

2nd Edition - October 21, 2016

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  • Author: Terry Kenakin
  • Paperback ISBN: 9780128037522
  • eBook ISBN: 9780128037539

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Description

Pharmacology in Drug Discovery and Development: Understanding Drug Response, Second Edition, is an introductory resource illustrating how pharmacology can be used to furnish the tools necessary to analyze different drug behavior and trace this behavior to its root cause or molecular mechanism of action. The concepts discussed in this book allow for the application of more predictive pharmacological procedures aimed at increasing therapeutic efficacy that will lead to more successful drug development. Chapters logically build upon one another to show how to characterize the pharmacology of any given molecule and allow for more informed predictions of drug effects in all biological systems. New chapters are dedicated to the interdisciplinary drug discovery environment in both industry and academia, and special techniques involved in new drug screening and lead optimization. This edition has been fully revised to address the latest advances and research related to real time kinetic assays, pluridimensional efficacy, signaling bias, irreversible and chemical antagonism, allosterically-induced bias, pharmacokinetics and safety, target and pathway validation, and much more. With numerous valuable chapter summaries, detailed references, practical examples and case studies throughout, Dr. Kenakin successfully navigates a highly complex subject, making it accessible for students, professors, and new researchers working in pharmacology and drug discovery.

Key Features

  • Includes example-based cases that illustrate how the pharmacological concepts discussed in this book lead to practical outcomes for further research
  • Provides vignettes on those researchers and scientists who have contributed significantly to the fields of pharmacology and drug discovery throughout history
  • Offers sample questions throughout the book and an appendix containing answers for self-testing and retention

Readership

Graduate students, new researchers and professors in pharmacology, as well as scientists (biologists or chemists) who foresee applying pharmacology to the discovery of new drug molecules from either industry or academic standpoints

Table of Contents

  • Chapter 1. Pharmacology: The Chemical Control of Physiology

    • Abstract
    • Pharmacology and Cellular Drug Response
    • New Terminology
    • Pharmacological Targets
    • Dose–Response Curves
    • Linking Observed Pharmacology With Molecular Mechanism
    • Descriptive Pharmacology: I
    • Summary
    • Questions
    • References

    Chapter 2. Drug Affinity and Efficacy

    • Abstract
    • Introduction
    • New Terminology
    • Agonist Selectivity
    • Affinity
    • Efficacy
    • Drugs With Multiple Efficacies
    • Quantifying Agonist Activity
    • Descriptive Pharmacology: II
    • Summary
    • Questions
    • References

    Chapter 3. Predicting Agonist Effect

    • Abstract
    • Agonist Response in Different Tissues
    • New Terminology
    • The Black–Leff Operational Model of Agonism
    • Applying the Black–Leff Model to Predict Agonism
    • Receptor Selectivity
    • Biased Agonist Signaling
    • Descriptive Pharmacology: III
    • Summary
    • Questions
    • References

    Chapter 4. Drug Antagonism: Orthosteric Drug Effects

    • Abstract
    • Bimolecular Systems
    • New Terminology
    • What Is Drug Antagonism?
    • Antagonist Potency
    • Mechanism(s) of Receptor Antagonism
    • Orthosteric (Competitive and Noncompetitive) Antagonism
    • Slow Dissociation Kinetics and Noncompetitive Antagonism
    • Partial and Inverse Agonists
    • Antagonist Effects In Vivo
    • Descriptive Pharmacology: IV
    • Summary
    • Questions
    • References

    Chapter 5. Allosteric Drug Effects

    • Abstract
    • Introduction
    • New Terminology
    • Protein Allosterism
    • Allosteric Phenotypes
    • Unique Effects of Allosteric Modulators
    • Detecting Allosterism
    • Quantifying Allosteric Effect
    • Descriptive Pharmacology: V
    • Summary
    • Questions
    • References

    Chapter 6. Enzymes as Drug Targets

    • Abstract
    • Introduction
    • New Terminology
    • Enzyme Kinetics
    • Enzymes as Drug Targets
    • Reversible Enzyme Inhibition
    • Irreversible Enzyme Inhibition
    • Allosteric Enzyme Modulation
    • Enzyme Activation
    • Intracellular Effects of Enzyme-Active Drugs
    • Summary
    • Questions
    • References

    Chapter 7. Pharmacokinetics I: Permeation and Metabolism

    • Abstract
    • The Importance of Drug Concentration
    • New Terminology
    • “Drug-Like” Properties of Molecules
    • Drug Absorption
    • Drug Metabolism
    • Oral Bioavailability
    • Summary
    • Questions
    • References

    Chapter 8. Pharmacokinetics II: Distribution and Multiple Dosing

    • Abstract
    • Drugs in Motion: In Vivo Pharmacokinetics
    • New Terminology
    • The Central Compartment and In vivo Clearance
    • Renal Excretion
    • Drug Distribution
    • In Vivo PK
    • Oral Bioavailability
    • Drug–Drug Interactions
    • Nonlinear Pharmacokinetics
    • Scaling Data to Predict Human Pharmacokinetic Behavior
    • Summary
    • Questions
    • References

    Chapter 9. In Vivo Pharmacology

    • Abstract
    • Whole Body Drug Response
    • New Terminology
    • The “Dose” in Dose–Response
    • What Constitutes Drug Response?
    • The Importance of Kinetics In Vivo
    • Summary
    • Questions
    • References

    Chapter 10. Safety Pharmacology

    • Abstract
    • Introduction
    • New Terminology
    • Safety Versus Toxicity
    • Safety Pharmacology
    • Early Safety Tests
    • Hepatic Toxicity
    • Summary
    • Questions
    • References

    Chapter 11. Pharmacology in Drug Discovery

    • Abstract
    • Introduction
    • Unique Aspects of Pharmacology in the Discovery Process
    • Target-Versus System-Based Discovery Strategies
    • Progression Scheme for Drug Discovery
    • Libraries and Molecules as Drug Sources
    • Pharmacological Assay Design
    • High-Throughput Screening
    • Lead Optimization
    • Drug Development
    • Summary
    • Questions
    • References

    Appendix A. Answers to Chapter Questions

    • Chapter 1
    • Chapter 2
    • Chapter 3
    • Chapter 4
    • Chapter 5
    • Chapter 6
    • Chapter 7
    • Chapter 8
    • Chapter 9
    • Chapter 10
    • Chapter 11

    Appendix B. Derivations and Proofs

    • Successive Saturable Functions Leads to Amplification of Signals
    • The Potency of a Full Agonist Depends on Both Affinity and Efficacy
    • Derivation of the Black–Leff Operational Model
    • Derivation of Variable Slope Black–Leff Operational Model
    • Derivation of the Gaddum Equation for Competitive Antagonism
    • Correction of IC50 to pKB for Competitive Antagonists
    • Derivation of the Equation for Noncompetitive Antagonism
    • Derivation of the Equation for Allosteric Modulation
    • Derivation of the Equation for Allosteric Modulation with Direct Agonism
    • Derivation of the Michaelis–Menten Equation for Enzymes

Product details

  • No. of pages: 350
  • Language: English
  • Copyright: © Academic Press 2016
  • Published: October 21, 2016
  • Imprint: Academic Press
  • Paperback ISBN: 9780128037522
  • eBook ISBN: 9780128037539

About the Author

Terry Kenakin

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

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