Pharmacology in Drug Discovery and Development

Understanding Drug Response

Terry P. Kenakin

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128037539
• Edition: 2
• Topic: Medicina
• Subtopic: Farmacologia

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.

• 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

Chapter 1

Pharmacology

The Chemical Control of Physiology

Abstract

This chapter discusses how drug response is quantified with dose–response curve and how this leads to classifications of drugs based on effect (ie, drugs that produce observed change in cellular processes are termed agonists and those that block such effects are antagonists). The dependence of observed potency of an agonist upon two drug-related parameters (affinity and efficacy) and two cell-dependent parameters (target density and efficiency of target coupling) is also discussed. The way that different tissues process drug stimulus to provide tissue response is considered, along with the null method which can be used to negate cell-dependent effects on drug activity to provide system-independent indices of drug activity. This is imperative in pharmacology as drugs are almost always studied in test systems, and not in therapeutic one(s).

Keywords

Affinity; agonists; antagonists; dose–response curves; efficacy; null method; potency

Outline

Pharmacology and Cellular Drug Response 1

New Terminology 2

Pharmacological Targets 4

Dose–Response Curves 7

Linking Observed Pharmacology With Molecular Mechanism 14

Descriptive Pharmacology: I 17

Summary 18

Questions 19

References 19

By the end of this chapter the reader should be able to understand how drug response is quantified by the use of dose–response curves, the way in which different tissues process drug stimulus to provide tissue response, and what qualifies a drug to be classified either as an agonist or antagonist.

Pharmacology and Cellular Drug Response

Pharmacology (from the Greek φάρμακον, pharmakon, “drug” and -λογ

α, -logia, the study of) concerns drug action on physiological systems (physiology from the Greek φ

σις, physis, “nature, origin” and -λογ

α, -logia is the study of the mechanical, physical and biochemical functions of living organisms). With regard to the application of pharmacology to the discovery of drugs for therapeutic benefit, the main focus of pharmacological theories, procedures and mechanisms relates to the chemical control of physiological processes. Insofar as the understanding of these physiological processes benefits the pharmacologic pursuit of drugs, pharmacology and physiology are intimately related. However, it will also be seen that complete understanding of the physiologic processes involved is not a prerequisite to the effective use of pharmacology in the drug discovery process. In fact, often an operational approach is utilized whereby the complexity of the physiology is represented by simple surrogate mathematical functions.

Historically, pharmacology evolved from the medical discipline of physiology (see Box 1.1) It should be stressed that pharmacology is the study of the molecule producing the physiological change (ie, the drug) and not the physiological change itself (although the latter is intimately involved with defining the nature of the drug). A unique feature of pharmacology is that the effect of the drug is often observed indirectly, that is, while the drug affects a select biochemical process in the cell, the outcome to an observer is an overall change in the state of the whole organism, and this is often the result of multiple interacting cellular processes. A major aim of pharmacology is to define the molecular events in initiating drug effects, since these define the action of drugs in all systems. If quantified correctly, this information can be used to predict drug effect at the pharmacological target in all systems including therapeutic one(s). While the ultimate aim of pharmacology in drug discovery is to define the therapeutic actions of drugs, the fact that drugs may have different behaviors in different organs depending on the state of the tissue means that it may not be possible to explicitly predict what a given drug will do in all tissues (since the state of these tissues in the human body may be quite heterogenous). Moreover, physiological and pathophysiological conditions may change the state of tissues making for even more heterogeneous therapeutic conditions. Therefore the drug discovery process of characterizing drug candidate molecules is aimed at defining what a given molecule has the capability of doing in a tissue, not necessarily what it will do in all tissues. For instance, one molecular activity an excitatory drug may have is to elevate the second cellular messenger cyclic adenosine monophosphate (AMP) through activation of a signaling protein called Gs Protein. If it can be shown that a given candidate molecule has no Gs protein stimulating activity, then it is known that this will not be a therapeutic outcome of the molecule. However, if the candidate does show Gs protein activating capability, this means that the molecule may elevate cyclic AMP therapeutically but only if the conditions are right to do so. The heterogeneity of tissues in the body also requires discovery efforts to utilize pharmacological concepts and procedures to convert descriptive data (what the experimenter sees in a particular experiment) into predictive data (enabling logical prediction of effects in other tissues). This is done through generic pharmacological scales such as affinity and efficacy (vide infra). At this point, it is useful to define what is meant by pharmacological target.

Box 1.1

The Birth of Pharmacology

Pharmacology may be considered the child of Physiology, itself an offspring of medicine. Historically, Physiology as a discipline is many hundreds of years old, beginning with pioneers such as the Greek physician Galen (129–200) and the English physician William Harvey (1578–1657). In their quest to understand the workings of the human body, early physiologists would probe systems with chemicals to see what changes occurred and how the body dealt with chemically-induced response. In time, a subset of these physiologists, such as Bernard (see below), became more interested in the probes than the systems and pharmacology was born.

I would in particular draw the attention to physiologists to this type of physiological analysis of organic systems which can be done with the aid of toxic agents…

Claude Bernard, Pharmacologist

The first Pharmacological Institute was created by Rudolf Buchheim (1820–79) in 1849 at the University of Dorpat in Estonia. The first Pharmacology Department in the United States was established by John Jacob Abel in 1891 at the University of Michigan School of Medicine.

New Terminology

The following new terms will be introduced in this chapter:

• Affinity: The propensity of a drug molecule to associate closely with a drug target.

• Agonists: Drugs that produce an observable change in the state of a physiological system.

• Antagonists: Drugs that may not produce a direct effect, but do interfere with the production of cellular response to an agonist.

• Dose–response curve: The relationship between doses (if the drug is used in vivo) or concentrations (if used in vitro) of a drug and pharmacologic effect.

• Drug target: The protein (or in some cases DNA, mRNA) to which a drug binds to elicit whatever pharmacologic effect it will produce. These proteins can be seven transmembrane (or one transmembrane) receptors, enzymes, nuclear receptors, ion channels or transport proteins.

• EC₅₀: Concentration of agonist producing half the maximal response to the same agonist; usually expressed for calculation and statistical manipulation as the pEC₅₀, negative logarithm of the molar concentration producing 50% response.

• Efficacy: The change in state of the drug target upon binding of a drug.

• Efficiency of target coupling: The relationship between the net quanta of activation given to a cell and the number of drug targets available for activation.

• Full agonists: Agonists that produce the full maximal response that the system can produce.

• Null method: The comparison of equiactive concentrations (or doses) of drug to cancel the cell-based processing of drug response. The assumption is that equal responses to a given agonist are processed in an identical manner by the cell.

• Partial agonists: Agonists that produce a maximal response that is of lower magnitude than the maximal response that the system can produce to maximal stimulation.

• pEC₅₀: The negative logarithm of EC₅₀ values. For arithmetic and/or statistical manipulation, numbers must be normally distributed. This is true only of pEC₅₀s, not of EC₅₀s; thus all averages, estimates or error and statistical procedures must use pEC₅₀.

• Potency: The concentration (usually molar...