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A Pharmacology Primer, 6e
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ACADEMIC
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A Pharmacology Primer
Techniques for More Effective and Strategic
Drug Discovery
Sixth Edition

Terry P. Kenakin
Professor of Pharmacology
The University of North Carolina School of Medicine
Chapel Hill, NC, United States
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 Dedication

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Contents
Preface to sixth edition xiii
2.6.3 Differences in receptor density 35
2.6.4 Target-mediated trafficking of
stimulus 37
1. What is pharmacology? 2.7 Receptor desensitization and
1.1 About this book 1 tachyphylaxis 37
1.2 What is pharmacology? 1 2.8 The measurement of drug activity 40
1.3 The receptor concept 3 2.9 Advantages and disadvantages of
1.4 Pharmacological test systems 4 different assay formats 40
1.5 The nature of drug receptors 7 2.10 Drug concentration as an independent
1.6 From the snapshot to the movie 7 variable 41
1.7 Pharmacological intervention and the 2.10.1 Dissimulation in drug
therapeutic landscape 8 concentration 41
1.8 System-independent drug parameters: 2.10.2 Free concentration of drug 43
affinity and efficacy 11 2.11 Chapter summary and conclusions 43
1.9 What is affinity? 13 2.12 Derivations 43
1.10 The Langmuir adsorption isotherm 14 2.12.1 Series hyperbolae can be
1.11 What is efficacy? 15 modeled by a single
1.12 Doseeresponse curves 17 hyperbolic function 44
1.12.1 Potency and maximal response 18 2.12.2 Successive rectangular hyper-
1.12.2 P-scales and the representation bolic equations necessarily
of potency 18 lead to amplification 44
1.13 Chapter summary and conclusions 20 2.12.3 Saturation of any step in a
1.14 Derivations: conformational selection stimulus cascade by two
as a mechanism of efficacy 20 agonists leads to identical
References 21 maximal final responses for
the two agonists 44
2. How different tissues process drug 2.12.4 Procedure to measure free
response drug concentration in the
receptor compartment 45
2.1 The ‘eyes to see’: pharmacologic assays 23 References 45
2.2 The biochemical nature of stimuluse
response cascades 25 3. Drugereceptor theory
2.3 The mathematical approximation of
stimuluseresponse mechanisms 27 3.1 About this chapter 47
2.4 Influence of stimuluseresponse 3.2 Drugereceptor theory 47
cascades on doseeresponse curve 3.3 The use of mathematical models in
slopes 29 pharmacology 48
2.5 System effects on agonist response: 3.4 Some specific uses of models in
full and partial agonists 30 pharmacology 49
2.6 Differential cellular response to 3.5 Mass action building blocks 55
receptor stimulus 33 3.6 Classical model of receptor
2.6.1 Choice of response pathway 33 function 56
2.6.2 Augmentation or modulation of 3.7 The operational model of receptor
stimulus pathway 34 function 57

vii
viii Contents

3.8 Two-state theory 58 4.7.3 Displacement of a radioligand

3.9 The ternary complex model 59 by an allosteric antagonist 92
3.10 The extended ternary complex model 59 4.7.4 Relationship between IC50 and
3.11 Constitutive receptor activity and KI for competitive antagonists 93
inverse agonism 60 4.7.5 Maximal inhibition of binding
3.12 The cubic ternary complex model 62 by an allosteric antagonist 94
3.13 Multistate receptor models and 4.7.6 Relationship between IC50 and
probabilistic theory 63 KI for allosteric antagonists 94
3.14 Chapter summary and conclusions 65 4.7.7 Two-stage binding reactions 94
3.15 Derivations 65 4.7.8 Effect of G-Protein coupling on
3.15.1 Radioligand binding to observed agonist affinity 94
receptor dimers demonstrating 4.7.9 Effect of excess receptor in
cooperative behavior 65 binding experiments: saturation
3.15.2 Effect of variation in an HIV-1 binding curve 94
binding model 66 4.7.10 Effect of excess receptor in
3.15.3 Derivation of the operational binding experiments: displace-
model 67 ment experiments 95
3.15.4 Operational model forcing 4.7.11 Derivation of an allosteric bind-
function for variable slope 67 ing model 95
3.15.5 Derivation of two-state theory 68 References 96
3.15.6 Derivation of the extended
ternary complex model 68 5. Drug targets and drug-target
3.15.7 Dependence of constitutive molecules
activity on receptor density 69
3.15.8 Derivation of the cubic ternary 5.1 Defining biological targets 97
complex model 69 5.2 Specific types of drug targets 100
References 69 5.2.1 G-protein-coupled receptors 100
5.2.2 Ion channels 102
5.2.3 Enzymes 103
4. Pharmacological assay formats:
5.2.4 Nuclear receptors 111
binding
5.2.5 Nucleotide-based drug targets 112
4.1 The structure of this chapter 71 5.3 Small drug-like molecules 114
4.2 Binding theory and experiment 71 5.3.1 Hybrid molecules 116
4.2.1 Saturation binding 74 5.3.2 Chemical sources for potential
4.2.2 Displacement binding 76 drugs 121
4.2.3 Kinetic binding studies 79 5.4 Biologics 126
4.3 Complex binding phenomena: agonist 5.4.1 Replacement proteins 127
affinity from binding curves 80 5.4.2 Eliminating ‘undruggable’ pro-
4.4 Experimental prerequisites for correct teins through PROTACs 130
application of binding techniques 84 5.4.3 Peptides 131
4.4.1 The effect of protein concentra- 5.4.4 Antibodies 135
tion on binding curves 84 5.4.5 Immunotherapy 141
4.4.2 The importance of equilibration 5.4.6 Vaccines 141
time for equilibrium between 5.4.7 Nucleic acidebased drug species 142
two ligands 85 5.5 Summary and conclusions 147
4.5 Binding in allosteric systems 87 References 147
4.6 Chapter summary and conclusions 91 Further reading 149
4.7 Derivations 92
4.7.1 Displacement binding: 6. Agonists: the measurement of affinity
competitive interaction 92 and efficacy in functional assays
4.7.2 Displacement binding:
noncompetitive interaction 92 6.1 Functional pharmacological
experiments 151
 Contents ix

6.2 The choice of functional assays 152 7.3.5 Analyses for partial agonists 201
6.3 Recombinant functional systems 156 7.3.6 The method of Lew and Angus:
6.4 Functional experiments: dissimulation nonlinear regression analysis 203
in time 159 7.4 Noncompetitive antagonism 204
6.5 Experiments in real time versus 7.5 Agonisteantagonist hemiequilibria 208
stop-time 160 7.6 Resultant analysis 210
6.6 Quantifying agonism: the BlackeLeff 7.7 Antagonism in vivo 210
operational model of agonism 162 7.7.1 Antagonists with efficacy in
6.6.1 Affinity-dependent versus vivo 212
efficacy-dependent agonist 7.7.2 Kinetics of target coverage 214
potency 166 7.7.3 Kinetics of dissociation 216
6.6.2 Secondary and tertiary testing 7.7.4 Estimating antagonist
of agonists 168 dissociation with hemiequilibria 219
6.7 Biased signaling 169 7.8 Blockade of indirectly acting agonists 219
6.7.1 Receptor selectivity 175 7.9 Irreversible antagonism 220
6.8 Null analyses of agonism 175 7.10 Chemical antagonism 222
6.8.1 Partial agonists 175 7.11 Chapter summary and conclusions 226
6.8.2 Full agonists 179 7.12 Derivations 227
6.9 Comparing full and partial agonist 7.12.1 Derivation of the Gaddum
activities: Log(max/EC50) 182 equation for competitive
6.10 Chapter summary and conclusions 183 antagonism 227
6.11 Derivations 183 7.12.2 Derivation of the Gaddum
6.11.1 Relationship between the EC50 equation for noncompetitive
and affinity of agonists 183 antagonism 227
6.11.2 Method of Barlow, Scott, and 7.12.3 Derivation of the schild
Stephenson for affinity of equation 228
partial agonists 184 7.12.4 Functional effects of an
6.11.3 Maximal response of a partial inverse agonist with the
agonist is dependent on operational model 228
efficacy 184 7.12.5 pA2 measurement for inverse
6.11.4 System independence of full agonists 228
agonist potency ratios 184 7.12.6 Functional effects of a partial
6.11.5 Measurement of agonist agonist with the operational
affinity: method of Furchgott 184 model 229
6.11.6 Agonism as a positive 7.12.7 pA2 measurements for partial
allosteric modulation of agonists 229
receptoresignaling protein 7.12.8 Method of Stephenson for
interaction to derive partial agonist affinity
DLog(max/EC50) ratios 185 measurement 229
References 187 7.12.9 Derivation of the Method of
Gaddum for noncompetitive
7. Orthosteric drug antagonism antagonism 230
7.12.10 Relationship of pA2 and pKB
7.1 Introduction 189
for insurmountable
7.2 Kinetics of drugereceptor interaction 189
orthosteric antagonism 230
7.3 Surmountable competitive antagonism 192
7.12.11 Resultant analysis 230
7.3.1 Schild analysis 192
7.12.12 Blockade of indirectly acting
7.3.2 Patterns of DoseeResponse
agonists 231
curves that preclude schild
7.12.13 Chemical antagonism:
analysis 197
abstraction of agonist
7.3.3 Best practice for the use of
concentration 231
schild analysis 198
7.12.14 Chemical antagonism:
7.3.4 Analyses for inverse agonists in
abstraction of antagonist
constitutively active receptor
concentration 231
systems 199
References 232
x Contents

8. Allosteric modulation 9.5.1 Predicting agonism 299

9.5.2 Predicting binding 301
8.1 Introduction 233 9.5.3 Drug combinations in vivo 302
8.2 The nature of receptor allosterism 233 9.6 Summary and conclusions 303
8.3 Unique effects of allosteric modulators 235 9.7 Derivations 304
8.4 Functional study of allosteric modulators 240 9.7.1 IC50 Correction Factors:
8.4.1 Phenotypic allosteric modulation competitive antagonists 304
profiles 242 9.7.2 Relationship of pA2 and pKB for
8.4.2 Allosteric agonism 243 Insurmountable Orthosteric
8.4.3 Affinity of allosteric modulators 243 antagonism 304
8.4.4 Negative allosteric modulators 246 9.7.3 Relationship of pA2 and pKB for
8.4.5 Positive allosteric modulators 250 Insurmountable Allosteric
8.4.6 Quantifying PAM activity in vivo 254 Antagonism 305
8.4.7 NAM/PAM induced agonist bias 255 References 305
8.4.8 Optimal assays for allosteric
function 255
10. Pharmacokinetics
8.5 Functional allosteric model with
constitutive activity 256 10.1 Introduction 307
8.6 Internal checks for adherence to the 10.2 Biopharmaceutics 307
allosteric model 257 10.3 The chemistry of “drug-like”
8.7 Methods for detecting allosterism 260 character 308
8.8 Chapter summary and conclusions 262 10.4 Pharmacokinetics 313
8.9 Derivations 262 10.4.1 Drug absorption 313
8.9.1 Allosteric model of receptor 10.4.2 Route of drug
activity 262 administration 319
8.9.2 Effects of allosteric ligands on 10.4.3 General pharmacokinetics 322
response: changing efficacy 263 10.4.4 Metabolism 325
8.9.3 Schild analysis for allosteric 10.4.5 Clearance 330
antagonists 263 10.4.6 Volume of distribution and
8.9.4 Application of Log(Max/R50) half-life 332
values from R50 curves to 10.4.7 Renal clearance 338
quantify the effects of PAMs 264 10.4.8 Bioavailability 340
8.9.5 Quantifying allosterically 10.5 Nonlinear pharmacokinetics 342
mediated induced bias in 10.6 Multiple dosing 343
agonism 264 10.7 Modifying pharmacokinetics through
8.9.6 Functional allosteric model with medicinal chemistry 345
constitutive receptor activity 265 10.8 Practical pharmacokinetics 347
References 266 10.8.1 Allometric scaling 349
10.9 Placement of pharmacokinetic assays
9. The optimal design of in discovery and development 350
pharmacological experiments 10.10 The pharmacokinetics of biologics 352
10.10.1 Absorption 353
9.1 Introduction 269 10.10.2 Duration of action 354
9.2 The optimal design of pharmacological 10.10.3 Antibody PK 355
experiments 269 10.10.4 mRNA PK 355
9.2.1 Drug efficacy 270 10.11 Summary and conclusions 355
9.2.2 Affinity 283 References 356
9.2.3 Orthosteric versus allosteric
mechanisms 292 11. Safety pharmacology
9.3 Null experiments and fitting data to
models 293 11.1 Safety pharmacology 359
9.4 Interpretation of experimental data 296 11.2 Hepatotoxicity 365
9.5 Predicting therapeutic activity in all 11.2.1 Drugedrug interactions 365
systems 299 11.2.2 Direct hepatotoxicity 370
 Contents xi

11.2.3 Hepatotoxicity in context in 13.2.3 Method of Furchgott for the

vivo 372 measurement of the affinity
11.3 Cytotoxicity 372 of a full agonist 428
11.4 Mutagenicity 374 13.2.4 Schild analysis for the
11.5 hERG activity and Torsades de measurement of competitive
Pointes 376 antagonist affinity 429
11.6 Autonomic receptor profiling and 13.2.5 Method of Stephenson for
off-target effects 376 measurement of partial
11.7 General pharmacology 377 agonist affinity 431
11.8 Clinical testing and drug toxicity 379 13.2.6 Method of Gaddum for
11.9 Summary and conclusions 381 measurement of noncom-
References 381 petitive antagonist affinity 433
13.2.7 Method for estimating affin-
12. The drug-discovery process ity of insurmountable antag-
onist (dextral displacement
12.1 Some challenges for modern drug
observed) 434
discovery 383
13.2.8 Resultant analysis for
12.2 The drug-discovery process 384
measurement of affinity of
12.3 Target-based drug discovery 384
competitive antagonists
12.3.1 Target validation and the
with multiple properties 436
use of chemical tools 385
13.2.9 Measurement of the affinity
12.3.2 Recombinant systems 388
and maximal allosteric
12.4 Systems-based drug discovery 390
constant for allosteric mod-
12.5 High-throughput screening 393
ulators producing surmount-
12.5.1 Structure-based drug design
able effects 436
and virtual screening 404
13.2.10 Method for estimating
12.5.2 Phenotypic screening 405
affinity of insurmountable
12.6 The lead optimization process 409
antagonist (no dextral
12.7 Drug effectiveness 413
displacement observed):
12.7.1 Clinical testing 414
detection of allosteric effect 438
12.7.2 Determining detailed profiles
13.2.11 Measurement of pKB for
of candidate efficacy 416
competitive antagonists
12.7.3 Assays in context 417
from a pIC50 441
12.7.4 Characterization of candidate
13.2.12 Statistical assessment of
efficacies 418
selectivity 442
12.8 Summary and conclusions 419
13.2.13 Measurement of surmount-
References 420
able allosteric antagonism 447
Further reading 422
13.2.14 Measurement of
insurmountable allosteric
13. Selected pharmacological methods antagonism (second
13.1 Binding experiments 423 method) 448
13.1.1 Saturation binding 423 13.2.15 Measurement of PAM
13.1.2 Displacement binding 423 activity 450
13.2 Functional assays 426 Reference 451
13.2.1 Determination of equiactive
concentrations on Dosee
Response curves 426
13.2.2 Method of Barlow, Scott,
Appendix 1: Statistics 453
and Stephenson for
measurement of the affinity Index 483
of a partial agonist 427
This page intentionally left blank
Preface to sixth edition
Pharmacologists almost always are working in systems
they do not fully understand. This has engendered a unique
“null system” of comparisons (before and after drug) that
has sustained the field. Our view of what is actually
happening in our experiment is obtained through our assay,
and as the Nobel Laureate Sir James Black wrote “.The
prismatic qualities of the assay distort our view in obscure
ways and degrees.” (1993; Nobel Lectures: Physiology
and Medicine). What this means to the discipline is that it is
uniquely dependent upon technology unveiling what we do
not understand about physiology and as technology ad-
vances the frontier of understanding, so too does the
perception of pharmacological mechanisms and the effect
of drugs on physiology. In essence, as the acuity of the
pharmacological prism improves, so too does our under-
standing of drug mechanisms. The practical outcome of this
is that a book on pharmacology must be updated every few
years to keep up with the new understanding gained from
technologies “new eyes to see.” This volume has been
updated and has added major chapters on biologics and the
drug discovery process that reflects the changing landscape
of drug therapy as well as views of historical findings
modified by new knowledge.
Terry P. Kenakin Ph.D.
Professor of Pharmacology,
The University of North Carolina School of Medicine,
Chapel Hill, NC, United States
xiii
This page intentionally left blank
Chapter 1
What is pharmacology?
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 ..
dClaude Bernard (1813e78).
1.1 About this book
Essentially this is a book about the methods and tools used in
pharmacology to quantify drug activity. Receptor pharma-
cology is based on the comparison of experimental data and
simple mathematical models, with a resulting inference of
drug behavior to the molecular properties of drugs. From this
standpoint, a certain level of understanding of the mathe-
matics involved in the models is useful but not imperative.
This book is structured such that each chapter begins with the
basic concepts and then moves on to the techniques used to
estimate drug parameters, and, finally, for those so inclined,
the mathematical derivations of the models used. Under-
standing the derivation is not a prerequisite for understanding
the application of the methods or the resulting conclusion;
these are included for completeness and are for readers who
wish to pursue exploration of the models. In general, facility
with mathematical equations is definitely not required for
pharmacology; the derivations can be ignored without any
detriment to the use of this book.
Second, the symbols used in the models and deriva-
tions, on occasion, duplicate each other (i.e., a is an
extremely popular symbol). However, the use of these
multiple symbols has been retained, since this preserves the
context of where these models were first described and
utilized. Also, changing these to make them unique would
cause confusion if these methods were to be used beyond
the framework of this book. Therefore, care should be taken
to consider the actual nomenclature of each chapter.
Third, an effort has been made to minimize the need to
cross-reference different parts of the book (i.e., when a
particular model is described, the basics are reiterated
somewhat to minimize the need to read the relevant but
different part of the book in which the model is initially
described). While this leads to a small amount of repeated
description, it is felt that this will allow for a more unin-
terrupted flow of reading and use of the book.
A Pharmacology Primer. https://doi.org/10.1016/B978-0-323-99289-3.00015-4
Copyright © 2022 Elsevier Inc. All rights reserved.
1.2 What is pharmacology?
Pharmacology (an amalgam of the Greek pharmakos,
medicine or drug, and logos, study) is a broad discipline
describing the use of chemicals to treat and cure diseases.
The Latin term pharmacologia was used in the late 1600s,
but the term pharmacum was used as early as the 4th
century to denote the term drug or medicine. In the Greek
translations “Pharmakeia” refers to Sorcery/Witchcraft
which no doubt was evident when particular herbal treat-
ments were effective. There are subdisciplines within
pharmacology representing specialty areas. Pharmacoki-
netics deals with the disposition of drugs in the human
body. To be useful, drugs must be absorbed and transported
to their site of therapeutic action. Drugs will be ineffective
in therapy if they do not reach the organs(s) to exert their
activity; this will be discussed specifically in Chapter 9,
Pharmacokinetics, of this book. Pharmaceutics is the study
of the chemical formulation of drugs to optimize absorption
and distribution within the body. Pharmacognosy is the
study of plant natural products and their use in the treat-
ment of disease. A very important discipline in the drug-
discovery process is medicinal chemistry, the study of the
production of molecules for therapeutic use. This couples
synthetic organic chemistry with an understanding of how
biological information can be quantified and used to guide
the synthetic chemistry to enhance therapeutic activity.
Pharmacodynamics is the study of the interaction of the
drug molecule with the biological target (referred to
generically as the “receptor,” vide infra). This discipline
lays the foundation of pharmacology since all therapeutic
application of drugs has a common root in pharmacody-
namics (i.e., as a prerequisite to exerting an effect, all drug
molecules must bind to and interact with receptors).
The history of pharmacology is tied to the history of
drug discoverydsee Chapter 9, The Optimal Design of
Pharmacological Experiments. As put by the Canadian
physician Sir William Osler (1849e919; the “father of
modern medicine”), “. the desire to take medicine is
perhaps the greatest feature which distinguishes man from
animals ..” Pharmacology as a separate science is
approximately 120e140 years old. The relationship be-
tween chemical structure and biological activity began to be
studied systematically in the 1860s [1]. It began when
1
2 A Pharmacology Primer
physiologists, using chemicals to probe physiological sys-
tems, became more interested in the chemical probes than
the systems they were probing. By the early 1800s, phys-
iologists were performing physiological studies with
chemicals that became pharmacological studies more aimed
at the definition of the biological activity of chemicals. The
first formalized chair of pharmacology, indicating a formal
university department, was founded in Estonia by Rudolf
Bucchiem in 1847. In North America, the first chair was
founded by John Jacob Abel at Johns Hopkins University
in 1890. A differentiation of physiology and pharmacology
was given by the pharmacologist Sir William Paton [2]:
If physiology is concerned with the function, anatomy with
the structure, and biochemistry with the chemistry of the
living body, then pharmacology is concerned with the
changes in function, structure, and chemical properties of
the body brought about by chemical substances
dW.D.M. Paton (1986).
Many works about pharmacology essentially deal in
therapeutics associated with different organ systems in the
body. Thus, in many pharmacology texts, chapters are
entitled drugs in the cardiovascular system, the effect of
drugs on the gastrointestinal (GI) system, the central ner-
vous system (CNS), and so on. However, the underlying
principles for all of these is the same, namely, the phar-
macodynamic interaction between the drug and the bio-
logical recognition system for that drug. Therefore, a
prerequisite to all of pharmacology is an understanding of
the basic concepts of doseeresponse and how living cells
process pharmacological information. This generally is
given the term pharmacodynamics or receptor pharma-
cology, where receptor is a term referring to any biological
recognition unit for drugs (membrane receptors, enzymes,
DNA, and so on). With such knowledge in hand, readers
will be able to apply these principles to any branch of
therapeutics effectively. This book treats doseeresponse data
generically and demonstrates methods by which drug ac-
tivity can be quantified across all biological systems irre-
spective of the nature of the biological target.
A great strength of pharmacology as a discipline is that
it contains the tools and methods to convert “descriptive
data,” i.e., data that serve to characterize the activity of a
given drug in a particular system, to “predictive data.” This
latter information can be used to predict that drug’s activity
in all organ systems, including the therapeutic one. This
defines the drug-discovery process which is the testing of
new potential drug molecules in surrogate systems (where a
potentially toxic chemical can do no lasting harm) before
progression to the next step, namely, testing in human
therapeutic systems. The models and tools contained in
pharmacology to convert drug behaviors in particular
organs to molecular properties (see Chapter 2: How
Different Tissues Process Drug Response) are the main
subject of this book, and the step-by-step design of phar-
macologic experiments to do this are described in detail in
Chapter 8, The Optimal Design of Pharmacological Ex-
periments (after the meaning of the particular parameters
and terms is described in previous chapters).
The human genome is now widely available for drug-
discovery research. Far from being a simple blueprint of
how drugs should be targeted, it has shown biologists that
receptor genotypes (i.e., properties of proteins resulting
from genetic transcription to their amino acid sequence) are
secondary to receptor phenotypes (how the protein interacts
with the myriad of cellular components and how cells tailor
the makeup and functions of these proteins to their indi-
vidual needs). Since the arrival of the human genome, re-
ceptor pharmacology as a science is more relevant than ever
in drug discovery. Current drug therapy is based on less
than 500 molecular targets, yet estimates utilizing the
number of genes involved in multifactorial diseases suggest
that the number of potential drug targets ranges from 2000
to 5000 [3]. Thus, current therapy is using only 5%e10%
of the potential trove of targets available in the human
genome.
A meaningful dialog between chemists and pharma-
cologists is the single most important element of the drug-
discovery process. The necessary link between medicinal
chemistry and pharmacology has been elucidated by
Paton [2]:
For pharmacology there results a particularly close rela-
tionship with chemistry, and the work may lead quite
naturally, with no special stress on practicality, to thera-
peutic application, or (in the case of adverse reactions) to
toxicology.
dW.D.M. Paton (1986).
Chemists and biologists reside in different worlds from
the standpoint of the type of data they deal with. Chemistry
is an exact science with physical scales that are not subject
to system variance. Thus, the scales of measurement are
transferable. Biology deals with the vagaries of complex
systems that are not completely understood. Within this
scenario, scales of measurement are much less constant and
much more subject to system conditions. Given this, a gap
can exist between chemists and biologists in terms of un-
derstanding and also in terms of the best method to progress
forward. In the worst circumstance, it is a gap of credibility
emanating from a failure of the biologist to make the
chemist understand the limits of the data. Usually, however,
credibility is not the issue, and the gap exists due to a lack
of common experience. This book was written in an
attempt to limit or, hopefully, eliminate this gap.
 What is pharmacology? Chapter | 1 3

1.3 The receptor concept
One of the most important concepts emerging from early
pharmacological studies is the concept of the receptor.
Pharmacologists knew that minute amounts of certain
chemicals had profound effects on physiological systems.
They also knew that very small changes in the chemical
composition of these substances could lead to huge dif-
ferences in activity. This led to the notion that something
on or in the cell must specifically read the chemical infor-
mation contained in these substances and translate it into a
physiological effect. This something was conceptually
referred to as the “receptor” for that substance. Pioneers
such as Paul Ehrlich (1854e915, Fig. 1.1A) proposed the
existence of “chemoreceptors” (actually he proposed a
collection of amboreceptors, triceptors, and polyceptors) on
cells for dyes. He also postulated that the chemoreceptors
on parasites, cancer cells, and microorganisms were
different from healthy host and thus could be exploited
therapeutically. The physiologist turned pharmacologist
John Newport Langley (1852e926, Fig. 1.1B), during his
studies with the drugs jaborandi (which contains the alka-
loid pilocarpine) and atropine, introduced the concept that
receptors were switches that received and generated signals
and that these switches could be activated or blocked by
specific molecules. The originator of quantitative receptor
theory, the Edinburgh pharmacologist Alfred Joseph Clark
(1885e941, Fig. 1.1C), was the first to suggest that the
data, compiled from his studies of the interactions of
acetylcholine and atropine, resulted from the unimolecular
interaction of the drug and a substance on the cell surface.
He articulated these ideas in the classic work The Mode of
Action of Drugs on Cells [4], later revised as the Handbook
of Experimental Pharmacology [5]. As put by Clark
It appears to the writer that the most important fact shown
by a study of drug antagonisms is that it is impossible to
explain the remarkable effects observed except by assuming
that drugs unite with receptors of a highly specific pattern
.. No other explanation will, however, explain a tithe of
the facts observed.
dA.J. Clark (1937).
Clark’s next step formed the basis of receptor theory by
applying chemical laws to systems of “infinitely greater
complexity” [4]. It is interesting to note the scientific at-
mosphere in which Clark published these ideas. The
dominant ideas between 1895 and 1930 were based on
theories such as the law of phasic variation essentially
stating that “certain phenomena occur frequently.” Ho-
meopathic theories like the ArndteSchulz law and
WebereFechner law were based on loose ideas around
surface tension of the cell membrane, but there was little
physicochemical basis for these ideas [6]. In this vein,
prominent pharmacologists of the day, such as Walter
Straub (1874e944), suggested that a general theory of
chemical binding between drugs and cells utilizing re-
ceptors was “. going too far . and . not admissible”
[6]. The impact of Clark’s thinking against these concepts
cannot be overemphasized to modern pharmacology.

FIGURE 1.1 Pioneers of pharmacology. (A) Paul Ehrlich (1854e915). Born in Silesia, Ehrlich graduated from Leipzig University to go on to a
distinguished career as head of institutes in Berlin and Frankfurt. His studies with dyes and bacteria formed the basis of early ideas regarding recognition
of biological substances by chemicals. (B) John Newport Langley (1852e926). Though he began reading mathematics and history in Cambridge in 1871,
Langley soon took to physiology. He succeeded the great physiologist M. Foster to the chair of physiology in Cambridge in 1903 and branched out into
pharmacological studies of the autonomic nervous system. These pursuits led to germinal theories of receptors. (C) Alfred J. Clark (1885e941). Beginning
as a demonstrator in pharmacology in King’s College (London), Clark went on to become Professor of pharmacology at University College London. From
there he took the chair of pharmacology in Edinburgh. Known as the originator of modern receptor theory, Clark applied chemical laws to biological
phenomena. His books on receptor theory formed the basis of modern pharmacology.
4 A Pharmacology Primer
It is possible to underestimate the enormous signifi-
cance of the receptor concept in pharmacology until it is
realized how relatively chaotic the study of drug effect
was before it was introduced. Specifically, consider the
myriad of physiological and pharmacological effects of
the hormone epinephrine in the body. As shown in
Fig. 1.2, a host of responses are obtained from the CNS,
cardiovascular system, smooth muscle, and other organs.
It is impossible to see a thread which relates these very
different responses until it is realized that all of these are
mediated by the activation of a single protein receptor,
namely, in this case, the b-adrenoceptor. When this is
understood, a much better idea can be gained as to how to
manipulate these heterogeneous responses for therapeutic
benefit; the receptor concept introduced order into physi-
ology and pharmacology.
Drug receptors can exist in many forms, including cell
surface proteins, enzymes, ion channels, membrane trans-
porters, DNA, and cytosolic proteins (see Fig. 1.3). There
are examples of important drugs for all of these. This book
deals with general concepts which can be applied to a range
of receptor types, but most of the principles are illustrated
with the most tractable receptor class known in the human
genome, namely, seven transmembrane (7TM) receptors
(7TMRs). These receptors are named for their characteristic
structure that consists of a single protein chain that tra-
verses the cell membrane seven times to produce extra-
cellular and intracellular loops. These receptors activate
G-proteins to elicit response, thus they are also
commonly referred to as G-protein-coupled receptors
(GPCRs); this should now be considered a limiting moniker
as these proteins signal to a wide variety of signaling
molecules in the cell and are not confined to G-protein
FIGURE 1.2 A sampling of the heterogeneous physiological and pharmacological response to the hormone epinephrine. The concept of receptors links
these diverse effects to a single control point, namely, the b-adrenoceptor.
effects. There are between 800 and 1000 [7] of these in
the genome [the genome sequence predicts 650 GPCR
genes, of which approximately 190 (on the order of 1% of
the genome of superior organisms) are categorized as
known 7TMRs [8] activated by some 70 ligands]. In the
United States, in 2000, nearly half of all prescription drugs
were targeted toward 7TM receptors [3]. These receptors,
comprising between 1% and 5% of the total cell protein,
control a myriad of physiological activities. They are
tractable for drug discovery because they are on the cell
surface, and therefore drugs do not need to penetrate the
cell to produce effect. In the study of biological targets such
as 7TMRs and other receptors, a “system” must be
employed that accepts chemical input and returns biological
output. It is worth discussing such receptor systems in
general terms before their specific uses are considered.
1.4 Pharmacological test systems
Molecular biology has transformed pharmacology and the
drug-discovery process. As little as 20 years ago, screening
for new drug entities was carried out in surrogate animal
tissues. This necessitated a rather large extrapolation to
span the differences in genotype and phenotype. The belief
that the gap could be bridged came from the notion that the
chemicals recognized by these receptors in both humans
and animals were the same (vide infra). Receptors are
unique proteins with characteristic amino acid sequences.
While polymorphisms (spontaneous alterations in amino
acid sequence, vide infra) of receptors exist in the same
species, in general the amino acid sequence of a natural
ligand-binding domain for a given receptor type largely
may be conserved. There are obvious pitfalls of using

FIGURE 1.3 Schematic diagram of potential drug targets. Molecules can affect the function of numerous cellular components both in the cytosol and on
the membrane surface. There are many families of receptors that traverse the cellular membrane and allow chemicals to communicate with the interior of
the cell.
surrogate species receptors for predicting human drug ac-
tivity, and it never can be known for certain whether
agreement for estimates of activity for a given set of drugs
ensures accurate prediction for all drugs. The agreement is
very much drug and receptor dependent. For example, the
human and mouse a2-adrenoceptors are 89% homologous
and thus considered very similar from the standpoint of
amino acid sequence. Furthermore, the affinities of the a2-
adrenoceptor antagonists atipamezole and yohimbine are
nearly indistinguishable (atipamezole human a2-C10
Ki ¼ 2.9  0.4 nM, mouse a2-4H Ki ¼ 1.6  0.2 nM;
yohimbine human a2-C10 Ki ¼ 3.4  0.1 nM, mouse a2-
4H Ki ¼ 3.8  0.8 nM). However, there is a 20.9-fold
difference for the antagonist prazosin (human a2-C10
Ki ¼ 2034  350 nM, mouse a2-4H Ki ¼ 97.3  0.7 nM)
[9]. Such data highlight a general theme in pharmacological
research, namely, that a hypothesis, such as one proposing
that two receptors which are identical with respect to their
sensitivity to drugs are the same, cannot be proven, only
disproven. While a considerable number of drugs could be
tested on the two receptors (thus supporting the hypothesis
that their sensitivity to all drugs is the same), this hypoth-
esis is immediately disproven by the first drug that shows
differential potency on the two receptors. The fact that a
series of drugs tested show identical potencies may mean
only that the wrong sample of drugs has been chosen to
unveil the difference. Thus, no general statements can be
made that any one surrogate system is completely predic-
tive of activity on the target human receptor. This will al-
ways be a drug-specific phenomenon.
The link between animal and human receptors is the fact
that both proteins recognize the endogenous transmitter
(e.g., acetylcholine, norepinephrine), and therefore the hope
What is pharmacology? Chapter | 1 5
is that this link will carry over into other drugs that
recognize the animal receptor. This imperfect system
formed the basis of drug discovery until human cDNA for
human receptors could be used to make cells express hu-
man receptors. These engineered (recombinant) systems are
now used as surrogate human-receptor systems, and the
leap of faith from animal receptor sequences to human-
receptor sequences is not required (i.e., the problem of
differences in genotype has been overcome). However,
cellular signaling is an extremely complex process and cells
tailor their receipt of chemical signals in numerous ways.
Therefore, the way a given receptor gene behaves in a
particular cell can differ in response to the surroundings in
which that receptor finds itself. These differences in
phenotype (i.e., properties of a receptor produced by
interaction with its environment) can result in differences in
both the quantity and quality of a signal produced by a
concentration of a given drug in different cells. Therefore,
there is still a certain, although somewhat lesser, leap of
faith taken in predicting therapeutic effects in human tis-
sues under pathological control from surrogate recombinant
or even surrogate natural human-receptor systems. For this
reason, it is a primary requisite of pharmacology to derive
system-independent estimates of drug activity that can be
used to predict therapeutic effect in other systems.
A schematic diagram of the various systems used in
drug discovery, in order of how appropriate they are to
therapeutic drug treatment, is shown in Fig. 1.4. As dis-
cussed previously, early functional experiments in animal
tissue have now largely given way to testing in recombinant
cell systems engineered with human-receptor material. This
huge technological step greatly improved the predictability
of drug activity in humans, but it should be noted that there
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 The Megalesian Games.
The Megalesian games were celebrated annually at Rome, in the
beginning of April, with solemn feasts, in honour of Cybele, otherwise
called Rhea, the mother of the gods. Opinions vary as to their
duration, some fixing it at six days, and others at not more than one.
Originally instituted in Phrygia, these ceremonies were introduced at
Rome, during the second Punic war, when the statue of the goddess
was carried thither from Pessinus. They consisted chiefly of scenic
sports; and women danced before this statue, which was held so
sacred, that no servant was allowed to approach it, or to take any
part in the games. They were called Megalesian, from the Greek
words, μεγαλη, great, Cybele being known by the name of the Great
Goddess, and Ευαλωσια, another name of Cybele, as presiding over
husbandry. The festival ΘΕΣΜΟΦΟΡΙΑ, celebrated in Athens,
Sparta, and Thebes, in honour of the same goddess resembled in
many circumstances the Roman Megalesia; the Latins appear to
have adopted partially, on various occasions, the religious
ceremonies of the Greeks, particularly in their imitation of certain of
the solemnities which were observed at the Eleusinian mysteries.

NOTE 48.

Curule Ædilate.
The Curule Ædiles, created in the year of Rome 388, were at first
elected from among the patricians. These magistrates were
appointed to inspect all public edifices, (whence their name) to fix the
rate of provisions, to take cognizance of disorders committed within
the city, and to examine weights and measures: but their chief
employment was to procure the celebration of the various Roman
games, and to exhibit comedies and shews of gladiators; on which
account, though inferior in rank to the Consuls, they precede them in
the title of this play. The Ædilate was an honourable office, and a
primary step to higher dignities in the republic. Curule magistrates
were those who were entitled to use the sella curulis, viz., the
consuls, prætors, curule ædiles, and censors: this chair was called
curulis, because those privileged to use it, always carried it in their
chariots, to and from the tribunals at which they presided. Tacitus
informs us in his annals (Book XIII. Chap. XXX.) that in the year 809,
the power of the Ædiles, both curule, and plebeian, was very much
circumscribed; that their salary was regulated anew; and limits fixed,
as to the sum they were allowed to impose as a fine.

NOTE 49.

Marcus Fulvius.
Son of the Consul for the year 564, and great grandson of the
illustrious Servius Fulvius Pætinus Nobilior, the companion of
Regulus; Pætinus was consul in the year 498. Marcus Fulvius
obtained the consulate eight years after his Ædilate: the name of his
colleague was Cneus Cornelius Dolabella. It is probable that this
branch of the Fulvian family assumed the agnomen of Nobilior, to
distinguish themselves as nobiles from the rest of the Fulvii, who
might not have had any claim to that title. None but those, and the
posterity of those, who had borne some curule office, (vide note 48)
were nobiles, or nobles. The nobiles possessed the exclusive right of
making statues of themselves; which were carefully preserved by
their posterity, and usually carried in procession on solemn
occasions: they painted the faces of these images

———————“Quid prodest, Pontice, longo

Sanguine censeri, pictosque ostendere vultus
Majorum.”

What avails it to be thought,

Of ancient blood? and to expose to view,
The painted features of dead ancestors?
Juvenal.

NOTE 50.
 Marcus Glabrio.
This person was doubtless distinguished by another appellation
which is not set down in the title to this play: under the name of
Glabrio, there is no account of him extant. As Glabrio does not
appear to have been the name of any Gens, or family in Rome, it
was probably the Agnomen of Marcus only, and not common to his
kindred.

NOTE 51.

By the company of Lucius Ambivius Turpio, and Lucius Attilius.

These were the principal actors of their company, but otherwise
persons of little note; for contrary to the customs of Greece, where
men of the highest rank thought it no degradation to appear on the
stage; the actors at the Roman theatres were not treated with that
consideration to which persons of talent, who furnish the public with
a polite and rational amusement, united with instruction, have a just
and undeniable claim. However unjust the Romans might have been
in this particular, they made an exception in favour of transcendent
merit; as in the case of the admirable Roscius, though the mention
made of this favourite performer by his friend Cicero, shews the truth
of the foregoing remark. “Cum artifex ejusmodi sit, ut solus dignus
videatur esse qui in scenâ spectetur; tum vir ejusmodi fuit, ut solus
dignus videatur qui non accedat;” so excellent an actor, that he only
seemed worthy to tread the stage, and yet so noble a man, that he
seemed to be the very last person that ought to appear there.
Though the Roman actors were not allowed their due privileges as
citizens, yet some of the most eminent were often very great
favourites with the people, and created so much interest among
them, that (as Suetonius tells us) the parties of rival performers
disputing for precedence, have proceeded so far as to terminate the
quarrel in bloodshed. Turpio and Attilius were actors of the first class,
and were said (vid. Terence Phorm:) agere primas partes, because
they always personated the principal characters in the piece.
 NOTE 52.

Præneste.
Præneste was a town of Latium, about twenty-four miles from
Rome, and founded by Cæculus, as we are told by Virgil, B. 7.

“Nec Prænestinæ fundator defuit urbis,

Vulcano genitumque omnis quem credidit ætas
Cæculus.”

Nor was the founder of Præneste absent,

Cæculus, the reputed son of Vulcan.

Præneste was deemed a place of military importance, from its

situation, and Cicero (in Catal.) tells us that Catiline, when foiled in
his attempt to seize the capital, endeavoured to make himself master
of Præneste. This town was particularly celebrated for very cold
springs, which were held in high esteem, as Strabo assures us, and
Horace mentions the circumstance in one of his odes.

“seu mihi frigidum

Præneste, seu Tibur supinum,
Seu liquidæ placuere Baiæ.”

NOTE 53.

Equal flutes right and left handed.

Flutes were called in Latin tibiæ, because they were made of the
shank or shin-bone of some animal, until the discovery of the art of
boring flutes, when they began to use wood,
“Longave multifori delectat tibia buxi.”—Ovid.
 The manner in which these instruments were played on the stage,
and the distinction of right- and left-handed flutes, has never been
ascertained with any degree of certainty: few subjects have more
obstinately baffled the researches of the learned. The most
perspicuous detail of all that the moderns are acquainted with
respecting the ancient flutes, is written by the learned Madame
Dacier, part of which is quoted in the Preface to this Translation.

NOTE 54.

It is taken from the Greek.

All Terence’s comedies were of this class, which was called
Palliatæ, viz., plays in which the scene was laid in Greece. The
class, called Togatæ, were pieces entirely Roman. The palliatæ were
generally new comedies, of which Menander was the inventor; but
Pacuvius wrote the middle, and Livius Andronicus the old comedy.
(Vide Note 33.) In the age in which Terence wrote his comedies, the
Romans were some degrees less advanced in the refinements of
civilization, than the Greeks. But little more than a century before,
Pyrrhus, king of Epirus, thought them worthy of no better epithet than
that of “barbarians” in comparison with his own subjects, who were
not themselves the most polished nation in the world. The Romans,
therefore, omitted no opportunity of improving the manners and
perfecting the education of their youth, by sending them to mix with
the Greeks, and to unite themselves to the disciples of those Grecian
sages, who, as far as the light of reason, unassisted by divine
revelation, could penetrate, dispelled the clouds of ignorance, and
taught their followers that happiness and wisdom can be attained
only by the virtuous. It was, doubtless, on this account, that Terence
chose Greece as the scene of his comedies, which he intended
should portray to the Romans the manners, customs, and characters
of those whom they often held up as a pattern of polished
refinement, worthy the imitation of the rising generation.
It is to this, doubtless, that we must attribute Terence’s choice of
Athens in preference to Rome as the scene of his plays; as,
particularly, in the comedy which the critics call the comedy of
intrigue, the best judges agree that the scene is preferably laid in that
country in which it is meant to be performed. But the comedies of
Terence were more of that description which Dr. Blair denominates
the comedy of character, and preferable to what he calls the comedy
of intrigue, because “it exhibits the prevailing manners which mark
the character of the age in which the scene is laid. Incidents should
afford a proper field for the exhibition of character: the action in
comedy, though it demands the poet’s care in order to render it
animated and natural, is a less significant and important part of the
performance than the action in tragedy; as, in comedy, it is what men
say, and how they behave, that draws our attention, rather than what
they perform or what they suffer.”

NOTE 55.

The consulate of Marcus Claudius Marcellus, and Cneus Sulpicius

Galba.
The consuls, the chief magistrates of the Roman republic were
first created at the expulsion of the kings in the year 244: they were
two in number, and chosen annually. The consuls were the head of
the Senate, which they assembled and dismissed at pleasure,
though it was not their exclusive privilege, as a dictator, his master of
the horse, the prætors, military tribunes, and even the tribunes of the
people, might also, on certain occasions, assemble the Senate. The
consuls, however, were the supreme judges of all differences; they
commanded the armies of the republic, and, during their consulate,
enjoyed almost unbounded power, which could only be checked by
the creation of a dictator, to whom the consuls were subordinate. It
was requisite that every candidate for the consulship should be forty-
three years of age, and that he should previously have discharged
the functions of Prætor, Ædile, and Quæstor. The consuls were
always patricians till the year 388, when, by the influence of their
tribunes, the people obtained a law, that henceforth one of them
should be a plebeian. The ensigns of consular dignity were twelve
guards, called lictors, (who bore the fasces,) and a robe, fringed with
purple, worn by these magistrates, during their consulate. The
names of the consuls are mentioned in the title of this play, merely to
fix its date, as the Roman method of reckoning their years was by the
names of the consuls. This custom continued for 1,300 years.
Marcus Claudius Marcellus was the grandson of the great Marcellus,
slain in the year 545; for Caius Sulpicius Galba, vide Note 27.

NOTE 56.

Prologue.
Madame Dacier grounds on the first line of this Prologue an
opinion, that the Andrian was not Terence’s first play: but, if that
learned and justly-celebrated lady had attentively considered the
relation the sixteen following lines of the Prologue bear to the first,
she could not have made this deviation from her usual extreme
accuracy. Whether the Andrian was, or was not, our Author’s first
production, is a question of more curiosity than real importance: it
has, however, undergone some discussion among the learned; and,
in my opinion, it may be clearly ascertained by an attentive perusal of
the Prologue to the Andrian, and learned and unlearned are equally
competent to decide upon it. Let us now examine the proof. The first
seven lines inform us, that “when the poet began to write, he thought
he had only to please the people, but that he finds it far otherwise; as
he is obliged to write a Prologue to answer the objections of an older
bard.”
If we stop here, it is natural enough to conclude, that in the
Prologue to the Andrian, he is alluding to censures passed on some
former play. But, if we look at the next nine lines we see that in the
prologue to the Andrian, he repels a censure not passed on any
former production, but on the Andrian itself. Listen, says he, to their
objections, which are, in short, that in the composition of this very
Andrian, he has made a confused mixture of two of Menander’s
plays. What allusion is made to any former writings? None: the
snarling criticisms of the older bard were directed only against the
Andrian. I imagine that the case was thus: Terence wrote the
Andrian, and procured its representation, probably without any
Prologue, (which was sometimes dispensed with, as we see in
Plautus,) the play, and its author, were, probably, cried down and
abused by this older bard and his admirers, who might envy the
visible superiority of Terence, who afterwards composed the
Prologue in question, to answer their objections. The reader is
referred for further proof, to Suetonius’s Life of Terence, a translation
of which is prefixed to this play.

NOTE 57.

To answer the snarling malice of an older poet.

According to Donatus, the name of this older bard was Lucius
Lavinius: but there can be little doubt but that name is a corruption of
Luscius Lanuvinus, the arch-enemy of Terence, whom he handles so
roughly in his Prologue to the Eunuch. Luscius was a poet of
considerable talent. Volcatius gives him the ninth place,

“Nono loco esse facilè facio Luscium.”

Luscius undoubtedly I make the ninth.

NOTE 58.

Menander wrote the Andrian and Perinthian.

The Perinthian (a fine comedy now lost) was so called from
Perinthus, a town of Thrace, the name of which was afterwards
changed to Heraclea, and that name is now corrupted to Herecli, or
Erekli, its present appellation. Erekli is a town in the Turkish province
of Romania, on the north of the sea of Marmora, and about sixty
miles from Constantinople. It is a place of some consequence from
its vicinity to the Turkish capital. For the Andrian, vide Note 69.

NOTE 59.
 They censure Nævius, Plautus, Ennius.
An account of Nævius has been given in Note 41, and of Plautus
in Note 42. Ennius was the tenth comic poet of Rome, according to
Volcatius, who says, “Antiquitatis causâ decimum addo Ennium.” If it
be true that Ennius was but the tenth in poetical merit, the greatest
glory of the nine who were above him, must have been the
distinguished honour of excelling this highly extolled poet. Ennius
was born in the year of Rome 515, and died in 585; though he
obtained the privileges of a Roman citizen, he was, by birth, a
Calabrian, as Ovid expressly tells us, and informs us, that his statue
was placed on the tomb of the Scipios, because he had so nobly
celebrated their renowned actions:

“Ennius emeruit, Calabris in montibus ortus,

Contiguus poni, Scipio, magne tibi.”

Ennius, among Calabrian mountains born,

Deserves, O Scipio, to be placed by thee.

The reader cannot become acquainted with the enthusiastic

admiration of the Romans for the brilliant performances of Ennius,
better than by a perusal of some of the many and great encomiums
passed on him by those who, though they lived after him, may be
called his competitors for literary fame. Cicero calls him,
“Ingeniosus, poeta et auctor valde bonus.”—A man of great
abilities and wit, and an admirable writer both of poetry and of prose.
Horace also

“Ennius et sapiens, et fortis, et alter Homerus.”

Ennius the wise, and strong, another Homer.

Quintilian speaks of him thus, “Ennium sicut sacros vetustate

lucos adoremus, in quibus grandia et antiqua robora jam non tantam
speciem habent quam religionem.”—We revere Ennius, as we revere
the groves, sacred for their antiquity, in which the great and ancient
oaks are not reckoned precious for their beauty, but because they
are consecrated to religious purposes.
Lucretius thus,

“Ennius————- primus amœno

Detulit ex Helicone perenni fronde coronam.”
Ennius first wore the never-fading crown,
Gain’d at the Muses’ seat, the pleasant Helicon.

And, lastly, Ovid,

“Ennius ingenio maximus, arte rudis.”

Ennius, the first in wit, though wanting art.

Ennius wrote tragedies, comedies, annals, &c., of which some

fragments remain: he died of the gout, brought on by drinking.
Horace tells us, that Ennius was in the habit of raising his
imagination by large draughts of wine, when he intended to write a
description of any warlike action.

NOTE 60.

Simo. Carry in these things directly.

What “those things” were, though a subject of no great
importance, has been discussed with extreme diligence by various
learned commentators, who have not a little differed in opinion. The
idea of a French commentator, who supposed Simo to allude to
furniture bought by him for his son’s wedding, is ridiculed by the
learned Madame Dacier, who has herself suffered the same
treatment under the hands of some of our English critics, for
interpreting them in the sense I have adopted. That Simo should
provide furniture for a marriage which he had but slight hopes of
negotiating at that time, is not very probable. But Athenian slaves
performed all domestic offices in their masters’ houses: and Sosia,
even after he became a freedman might have practised cookery, in
which, perhaps, he excelled. He uses the words “mea ars,” my art,
and Simo answers him with “isthac arte,” that art, by which it is clear
that he means some particular art. The word art has in English both a
general and particular sense; but, in Latin, “ars” is generally used
only in the latter.
“Rara quidem facie, sed rarior arte canendi.”—Ovid.

Her beauty charms us; and oh! how much more

Her matchless skill in arts of melody.

Again,

“Hac arte Pollux, et vagus Hercules

Innixus, arces attigit igneas.”—Horace.

Supported by this art,

Pollux and Hercules were raised to heaven.

Sosia speaks in this character also at the end of the scene, “Sat
est curabo,” curo, meaning to cook; he uses also more than once the
word rectè, which is peculiarly a term of cookery, thus “rectiùs
cœnare,” Plautus; and, at Rome, when patrons invited their clients
or followers to supper, where a very plentiful banquet was always
served up: the supper was particularly designated Cœna recta. The
art of cookery, in Greece, was, in the earlier ages, far from being
accounted degrading, and was, indeed, frequently practised by men
very far above a servile station.
I mention this, lest those who are unacquainted with these
customs, might object against our author, that Simo was guilty of an
inconsistent condescension, in making a confidant of one who held
an office of this nature.

NOTE 61.

When I first bought you as my slave.

Slaves, among the Greeks, formed a very considerable portion of
the population of a city, and, in some places, were more numerous
than the citizens themselves. In Athens, all domestic offices were
performed by slaves, who were employed also in the capacities of
tutors, scribes, stewards, overseers, and husbandmen, according to
their respective talents: when a slave manifested great abilities, he
was taught the art or science for which he seemed most fitted. Some
were instructed in literature, and often so distinguished themselves
by their writings, that they obtained their freedom. The slaves of the
Athenians were either taken in war, or purchased, or reduced to
slavery for some crime: they were divided into two classes: 1. those
who were natives of some part of Greece, who had the privilege of
redeeming themselves; who, if cruelly treated, might appeal to the
archons, and change their master; and whose lives were not in their
master’s power; 2. those slaves who were transported from
barbarous nations, who were wholly at the disposal of their owners in
every respect. The price of a slave varied according to his
qualifications; some were worth about 10l. sterling, some were
valued at 20l., and others much higher. The Athenians were
celebrated for the gentleness with which they treated their slaves.
Xenophon informs us, that they frequently spoiled them by excessive
indulgence. Slaves were made free, if they rendered any essential
service to the government; and frequently received their liberty as a
reward for their fidelity and attachment to their master, and his family.
For further information respecting the Athenian slaves, and remarks
on their habits and manners, vide Notes 62, 63, 64, 68, 86, 88, 110,
131, 154ᴮ, 195, 196.
 NOTE 62.

I gave you freedom.

The ceremony of Ἀπελεύθερια, or giving a slave his liberty, was
performed in Athens as follows, the slave kneeled down at the feet of
his master, who struck him a slight blow, saying, “Be free;” or he took
the slave before a magistrate, and there formally declared him at
liberty. These ceremonies were extremely similar to those used by
the Romans on the same occasion. The Greeks sometimes set their
slaves at liberty in a public assembly, which Æschines describes as
follows, Ἄλλοι δέ τινες ὑποκηρυξάμενοι, τοὺς αὑτῶν οἰκέτας ἀφίεσαν
ἀπελευθέρους, μάρτυρας τῆς ἀπελευθερίας τοὺς Ἕλληνας
ποιούμενοι.”—Others, when they had obtained silence by means of
the heralds, gave their household slaves their liberty; and made the
assembled Greeks witnesses of their manumission.
The same author mentions a very singular law, which stigmatized
with infamy any person who should proclaim the freedom of a slave
in the theatre. “Καὶ διαῤῥήδην ἀπαγορεύει μήτε οἰκέτην
ἀπελευθεροῦν ἐν τῷ θεάτρῳ――――――――ἢ ἄτιμον εἶναι τὸν
κήρυκα.”—And this law clearly forbids that any person shall manumit
a slave in the theatre————-and decrees infamy to the herald who
shall proclaim his freedom there.
Slaves were called οἰκέται, and πελάται, but, after they became
free, received the appellation of ἀπελεύθεροι, and enjoyed all the
privileges granted to the νόθοι, or illegitimate citizens, who were not
admitted to all the rights of those whose parents were both freeborn
Athenian citizens. It was usual for a freedman to continue with his
master, who was called his προστατης, or patron; he was also
allowed to choose a sort of guardian, who was called ἐπίτροπος.

NOTE 63.

Nor have you given me any cause to repent that I did so.
An emancipated slave was bound to perform certain services for
his former master: he was to assist him in any emergency to the
utmost of his power: and, if he proved remiss in these duties, was
liable to a severe punishment. No freedman could appear in a court
of justice against his patron, either to give evidence in his own suit,
or in that of another.

NOTE 64.

It pains me to be thus reminded of the benefits you have conferred

upon me, as it seems to upbraid me with having forgotten them.
By the Athenian laws, any freedman convicted of ingratitude to his
former master, was reduced a second time to a state of slavery: but,
if a freedman was brought to a trial on a charge of this nature, and
acquitted of it, he was declared τελέως ἐλεύθερος, perfectly free, and
was then wholly released from all obligations of service to his former
patron.

NOTE 65.

You shall hear every thing from the beginning.

This is the initium narrationis, the first part of the narration, and, by
far the longest: it is, in the original, inimitably beautiful. Scarcely any
branch of dramatic writing is more difficult than narration, which,
unless composed in that happy vein, attainable by so few, generally
proves embarrassing to the actor, and tiresome to the auditors. The
writings of Terence abound with narrations, a necessary
consequence of his strict adherence to the unities. A judicious
French writer, whose opinions (as a critic,) have ever been treated
with deference, speaking of our author’s excellence in this branch of
the drama, makes his eulogium in just and forcible terms.
“Terence is without a rival, especially in his narrations,
which flow along with a smooth and even course, like a clear
and transparent river. We see no parade of sentiment, no
glare of obtrusive wit: no smart epigrammatical sentences,
which Nicole and Rochefoucault only can make acceptable.
 When he applies a maxim, it is in so plain and familiar a
manner, that it has all the simplicity of a proverb. He
introduces nothing but what appertains to the subject. I have
perused, and re-perused the writings of this poet with the
greatest attention, and have laid them aside with the
impression that there is not a scene too much in any play, nor
a line too much in any scene.”
Diderot on dramatic poetry.
For further remarks on the narrations of the Andrian, vide Notes.
Nos. 89. 95. 101. I shall postpone a continuance of observations on
the very obvious inconvenience attendant on narrations; and pursue
a remark made in the commencement of this note, respecting the
source from which has flowed so many of these narrations, which
require all the art and wit of a Terence to prevent them from seeming
too prolix.
This source may be found in those irksome unities of time and
place, those leaden fetters of dramatic genius, which, by chaining
down the imagination and talents of many of the ancient, and even
some of the modern, dramatic writers, have deprived the world of
more, than the embellishments they may have given to composition
can ever repay.
Terence, in all his works, in compliance with the reigning taste of
his age, observed the unities of action, time, and place, with the most
scrupulous exactness: and this observance is the chief reason that
his comedies can never succeed on any modern stage. His plays are
crowded with narratives, which, however beautifully written, will
never yield that attraction to an audience, which they find in busy and
lively action. He cannot bring on the stage what is supposed to
happen in the next street, or adjoining house, it must therefore be
related. All the story of the piece must be supposed to pass in a very
few hours: all those events which cannot be imagined to take place
in one day, and which, when represented to the spectators in the
modern drama, are often of the greatest interest, must, by the law of
the unity of time be related. Of what a scene, to instance one of
many, has the unity of place robbed us in Terence’s Eunuch! where
Laches (Act 5) rushes into the house of Thais. How many modern
plays, in which the unities were preserved, ever kept the stage a
month? None: if we except Ben Jonson’s “Silent Woman,” “The
Adventures of Five Hours,” and a very few others; and it may well be
doubted whether even our immortal Shakspeare himself, if he had
shackled his genius with these rules, would not have been generally
confined to the closet. The practice of that great poet, and of most of
the modern dramatists of all countries; who have observed only (the
rule of all stages, ancient and modern,) unity of action, is a tacit
condemnation of the other two: and the fiat of Dr. Johnson speaks a
yet plainer language. He has decided on the value of the unities in
his preface to Shakspeare: and though what he has written
respecting them is too long to be inserted here, the following extracts
will not be unacceptable, as they shew the grounds on which it is
assumed that dramatic writers ought, in general, to dispense with the
unities of time and place.
“The critics hold it impossible, that an action of months or years
can be possibly believed to pass in three hours. The spectator, who
knows that he saw the first act at Alexandria, cannot suppose that he
sees the next at Rome; he knows that he has not changed his place,
and that the place cannot change itself; that what was a house can
never become a plain; that what was Thebes, can never be
Persepolis. Such is the triumphant language with which a critic exults
over the miseries of an irregular poet; it is time, therefore, to tell him,
that he assumes as an unquestionable principle, a position, which,
while his breath is forming it into words, his understanding
pronounces to be false. It is false, that any representation is
mistaken for reality; that any dramatic fable, in its materiality was
ever credible, or, for a single moment, was ever credited. The
objection arising from the impossibility of passing the first hour at
Alexandria, and the next at Rome, supposes that when the play
opens, the spectator really imagines himself at Alexandria; and
believes that his walk to the theatre has been a voyage to Egypt, and
that he lives in the days of Antony and Cleopatra. Surely he that can
imagine this may imagine more. He that can take the stage at one
time for the Palace of the Ptolemies, may take it in half an hour for
the promontory of Actium: delusion, if delusion be admitted, has no
certain limitation. The truth is, that (judicious) spectators are always
in their senses, and know from the first act to the last, that the stage
is only a stage, and that the players are only players: and by
supposition as place is introduced, time may be extended.” Dr.
Johnson concludes this subject as follows; “He that, without
diminution of any other excellence, shall preserve all the unities
unbroken, deserves the like applause with the architect, who shall
display all the orders of architecture in a citadel, without any
deduction from its strength; but the principal beauty of a citadel is to
exclude the enemy; and the greatest graces of a play are to copy
nature, and instruct life.”
It is needless to add any thing to these arguments, as they must
be deemed conclusive. The plays of our author are better calculated,
perhaps, to please in the closet by his mode of writing, as it adds to
perspicuity: Terence is, probably, the greatest practical champion for
the three unities that ever did, or ever will, exist. His easy flowing
narratives, judiciously divided, and introduced with so much art, as in
some places to seem no narratives until they are concluded, remedy
as much as possible the inconveniences attendant on this mode of
writing.

NOTE 66.

When my son Pamphilus arrived at man’s estate.

In the Latin, postquam excessit ex Ephebis, after he was removed
from the class of young men called ἔφηβοι.
All the Athenian citizens were publicly registered three several
times. 1. In their infancy, on the second day of the festival
ἀπατούρια, called ἀνάῤῥυσις. 2. When they were 18 years of age,
they were registered on the third day of the ἀπατούρια, called
κουρεῶτις, when they received the title of ἔφηβοι. 3. At 20 years of
age, they were registered for the last time at the feast called
βενδίδεια on the 19th of the month, Thargelion, when they were said
to be admitted “among the men.” These ceremonies were used to
prevent the intrusion of persons, who had no claim to the title of
Athenian citizen, which was an honour, that even foreign kings
thought worthy of their pursuit. Having quitted the class of the
ἔφηβοι, Pamphilus, at the time mentioned by Simo, must have been
20 years of age.

NOTE 67.

The schools of the Philosophers.

Several schools of Philosophy were established at Athens, in
which philosophers of different sects presided, and gave instructions
to those of Athens, and of other countries, whose fortunes allowed
them leisure to pursue studies of this nature. The buildings in which
the philosophers delivered their lectures were provided at the public
expense: they were called Gymnasia, and built in divisions, some for
study called στοαὶ, and others for various exercises, as wrestling,
pugilism, dancing, &c.; these were denominated παλαίστρα. The
principal Gymnasia in Athens were the Lyceum, where Aristotle
taught; the academy, in which Plato presided; and, lastly, the
Cynosarges, which gave the name of Cynics to that sect of
philosophers, founded in this place by Antisthenes. (vid. Plutarch’s
Life of Themistocles).

NOTE 68.

In these times flattery makes friends; truth, foes.

Madame Dacier has elucidated this passage in an elegant and
ingenious criticism, which clears Pamphilus from the charge of
flattery which Sosia appears to insinuate against him. The sentence
in the original runs thus: “namque hoc tempore obsequium amicos
veritas odium parit.” “When Simo spoke of the obliging temper of his
son, he intended to describe him as behaving with that complaisant
politeness which is as remote as possible from flattery; the practice
of which never requires of a man any thing inconsistent with the laws
of truth and candour; otherwise he would have blamed his son,
instead of praising him. But Sosia, following the example of people of
his own rank, who always look on the dark side of every thing, takes
this opportunity of censuring the manners of the age, by declaring
that people were unwilling to hear the truth. Thus he mistakes
obsequium, which really means an amiable mildness of manners, for
assentatio, servile flattery, a vice which shows weakness of mind,
and baseness of heart: and which renders those of our friends who
practise it, more dangerous than even our enemies themselves.
There is more ingenuity in this passage than appears at first sight.”
Madame Dacier.
For some further very valuable critical observations, the reader is
referred to the preface to a translation of Phædrus’s fables,
published at Paris, about the middle of the 17th century. Besides
very able remarks on the Andrian, and the rest of Terence’s plays,
the translator gives an ingenious comparison between fable and
comedy; he also translated into French, three of Terence’s comedies,
viz., The Andrian, The Brothers, and Phormio.

NOTE 69.

The Island of Andros.

This island is situated in the Ægean sea, or, as it is now called,
the Archipelago; it is distant from the Piræus, or port of Athens, about
500 of the stadia Olympica, or rather more than 50 English miles. It
retains its original appellation. Bacchus seems to have been the
reputed patron of this island; which was also called Antandros, and
has been mistaken by some for the Antandros of Phrygia Minor,
where Æneas built his fleet. Vide Ovid’s Meta. Book 13, l. 623 to
670.

NOTE 70.

The neglect of her relations.

The relations of unmarried women in Greece were bound by law
to provide for them, either by seeing them married to some suitable
person, or to furnish them with the means of support according to
their rank in life; or if a woman had no near kindred, this duty
devolved upon a guardian called κυριος. It is probable that this
obligation extended equally to the paternal and maternal relations,
though the latter generally acted only in case of the former becoming
extinct. Terence warrants the supposition of relations on both sides,
being compelled to act, as he uses the word cognatus, which
signifies strictly a relation by the mother’s side, agnatus, on the
contrary, is never employed but to designate a kinsman by the
father’s side, though cognatus is often used as a common term for
both; and such is its meaning in this passage: for if the law had been
confined to the father’s relations, Terence would certainly have used
agnatus, and thereby clearly designated the particular persons who
were bound to observe it.

NOTE 71.

The distaff and the loom.

The Greek and Roman women led generally very domesticated
lives, and passed a considerable portion of their time in spinning and
weaving. The simple manners of the earlier ages obliged each family
to depend, in a great measure, on itself, for the supply of its various
wants, and the kings and heroes of antiquity, might doubly prize a
mantle or a vest, wrought by the hands of those who were dearest to
them. Wool was usually worn; but linen, though highly valued, seems
to have been but rarely used. When the Greeks became more
refined, this simplicity of manners among women of rank gave place
to less laborious habits, and slaves were instructed in the art of
spinning and weaving.

NOTE 72.

Several lovers made their addresses to her, &c.

This passage has been elegantly and chastely softened by an
ingenious French writer, who flourished about the year 1650. I shall