B O O K S
Pharmacologic Analysis of
DrugReceptor Interaction
(3rd edn)
by T. Kenakin, Lippincott-Raven,
1997. $104.00 (xiii 1 491 pages)
ISBN 0 397 51815 3
It would be useful to have a book
on the principles of drugreceptor
interaction to which students could
refer, and Kenakins book asks many
of the right questions. For example,
it addresses issues such as how well
does a drug bind to a receptor?, how
well does it activate the receptor
once it has bound?, how can we
measure these things? and how
can measurements of drug action
aid understanding of transduction
mechanisms and drug develop-
ment? These questions are central to
pharmacology. They are also central
(although this is not discussed) to
understanding the effects of mu-
tations in receptors, and hence to
understanding the function of pro-
tein domains (e.g. where is the bind-
ing site?). Many of these questions
have been answered with some
degree of quantitative success for
agonist-activated ion channels, which
are simpler than G protein-coupled
receptors (GPCRs). Therefore, it is
surprising that the book ignores all
the evidence from ion-channel work,
and deals almost entirely with
GPCRs.
So, if the right questions are asked,
what about the answers? Chapter 1
goes through the usual list of mod-
els, including occupation theory,
Stephenson, the operational model,
rate theory, two-state theory and
ternary complex models. But it is not
made clear which ones are merely
history (occupation), which ones
are wrong in principle (Stephenson;
operational model), which are curi-
osities that live on only in textbooks
like this (rate theory), what the re-
lationship between the theories is
and, most importantly, what evidence
exists for them. Incorrect assump-
tions are listed without comment,
and no attempt is made to relate the
various approaches (e.g. it is not
pointed out that Stephenson and
operational models are identical
apart from one extra assumption in
the latter). One almost comes away
with the impression that the choice
between theories is a matter of the
aesthetics and personal preference,
rather than of truth and falsehood.
This approach is apparent through-
out the book. For example, on p. 272
we are told that measurements of
full-agonist affinity can be made by a
procedure developed by Furchgott;
the method is then described in the
standard way, without qualification.
But the next section, confusingly,
goes on to point out that the method
doesnt work; this would have been
better explained at the outset.
There is, in many places, a blurring
of the essential distinction between
empirical curve fitting and physical
reality. The Hill equation is used
extensively (although it is referred
to, incorrectly, as the logistic equa-
tion), but its basis and its lack of
physical meaning are not explained.
Worse still, the old chestnut of
the general form of the Gaddum
equation is described uncritically
(p. 336). From time to time, it has
been suggested that this allows
analysis of competitive antagonism
when n molecules of agonist and m
molecules of antagonist interact with
the receptor. This equation lacks a
physical basis and certainly cannot
be expected to provide useful infor-
mation, but there is no indication of
this in the book. It is an error that
results from mistakenly taking the
Hill equation as a description of
physical reality rather than a con-
venient empirical description.
There are a number of other errors reactant, not because there are two
too. For example, on p. 248 the Adair
equation is given. This describes the
binding of a ligand to a molecule
with n binding sites. If the micro-
scopic equilibrium constants for
each step are equal then it reduces
exactly to the Langmuir equation1.
However, Kenakin writes the Adair
equation in its original form with
macroscopic equilibrium constants,
and thus appears to have to make
an approximation to obtain the
Langmuir equation from it. As well
as being wrong, this misses a good
opportunity to explain the difference
between microscopic and macro-
scopic constants.
In the chapter on statistical meth-
ods, there is a section on non-linear
curve fitting, and this is to be wel-
comed because it is a topic that is not
dealt with extensively in elementary
statistics books. Unfortunately, this
section begins by confusing the sep-
arate issues of Gaussian distribu-
tions and unequal variances at
different points on the curve (hetero-
scedasticity), and the method for
dealing with the latter (weighted
least squares) is not mentioned,
although it is available in many com-
mercial curve-fitting packages. It is a
pity that it was not discussed prop-
erly here, because the manuals for
the commercial packages appear to
have been written by people who
know more about animated icons
than statistics, and are usually
incomprehensible.
Finally, on p. 261, the description
of the predictions of the ternary com-
plex model seems to fall into the trap
of thinking that, because there are
two receptor species with agonist
bound (with and without the G pro-
tein bound), this means we expect to
see two-component binding curves.
This is not the case. If there is plenty
of G protein present, then we expect
simple Langmuirian agonist bind-
ing. If the supply of G protein is lim-
ited then its concentration will fall as
agonist binds and the binding curve
will be smeared out and shallow
(an example is shown in Fig. 8.11,
but not explained). However, this
happens because of depletion of a
sorts of binding site.
Almost all of the book is con-
cerned with equilibria, a result, no
doubt, of its focusing on GPCRs
(measurement of rates has largely
been confined to ion channels). The
final chapter deals with kinetics
and mentions some of the problems
involved in measuring and inter-
preting rates. On p. 442 it is stated
that checking that the measured
ratio of rates agrees with the
TiPS December 1998 (Vol. 19) 515
 B O O K S
independently determined equilib-
rium constant can solve the problem
of diffusion-limited rates. Unfortu-
nately, there is no mention that this
check does not work if an intact tis-
sue is used and, as is often the case,
the diffusion rate is slow because of
the binding of drug to the receptors
as it diffuses. In this case, both
numerator and denominator will be
wrong by much the same factor and
the check is useless.
Proinflammatory and
Antiinflammatory Peptides
edited by Sami I. Said,
Marcel Dekker, 1998. $195.00
(xxviii + 711 pages)
ISBN 0 8247 0120 8
It is increasingly emerging that
cytokines are not the only peptides
that facilitate or inhibit inflam-
mation, as they are joined by a grow-
ing number of neuropeptides that
can also influence the cellular sys-
tems involved in the inflammatory
process. To devote a whole book to
these inflammation-related peptides
is hence a worthwile enterprise that
provides novel perspectives on
understanding and treating inflam-
mation. However, when I read that
the book (Vol. 112 in the Lung
Biology in Health and Disease series)
was based on a FASEB symposium
held in 1995, I was about to dis-
respect it as another volume of meet-
ing proceedings with their often
fragmentary and unsteady treat-
ment of a subject. I changed my
attitude, though, when I realized
that the 711-page book contains an
88-page author index listing all
authors that are referenced any-
where in the 23 chapters plus a
17-page subject index. Thus, con-
siderable effort has gone into mak-
ing the book a useful source of refer-
ence, and this impression is borne
out by most of the chapters.
516 TiPS December 1998 (Vol. 19)
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On the positive side, Kenakins
book includes a large number of pic-
tures of experimental results (with a
strong bias to work on isolated tis-
sues), and a good account of the
complications that beset the study of
competitive antagonists in whole tis-
sues. Nevertheless, I have to say that
I could not recommend it to our
final-year students who would, I
fear, end up even more confused
than they already are. I say this with
Evidently, as the book is part of a
series on lung biology, the respira-
tory tract is the organ of primary
interest, although other systems
are also considered if appropriate.
Among the pro-inflammatory neuro-
peptides, tachykinins (substance P
and neurokinin A) take an important
place, as they are released by irrita-
tive stimuli from sensory nerve
fibres and can cause broncho-
constriction, increase vascular per-
meability, facilitate leukocyte adher-
ence and emigration, and stimulate
mucus secretion. In paying tribute to
their advanced status of preclinical
investigation, tachykinins are exten-
sively dealt with in six chapters
which suffer from some redundancy
as far as their molecular biology and
receptor pharmacology are con-
cerned. Some overlap is also inher-
ent in the two chapters on endo-
thelins, which review the recent
progress in this field, as does the
chapter on kinins.
A particular highlight of the book
is its emphasis on the fact that
inflammation, after being initiated
by pro-inflammatory mediators,
normally abates with time, a process
that appears to be defective if
chronic inflammation is to develop.
Apoptosis of inflammatory cells is
discussed to be an important
mechanism by which inflammation
is brought to an end, and it is pro-
posed that strategies to induce selec-
tive inflammatory cell apoptosis
could lead to novel approaches for
therapeutic gain. The book articles
real regret, because if there existed a
clear and reliable textbook in this
area it would save me a lot of time in
writing handouts.
David Colquhoun
Department of Pharmacology,
University College London,
Gower Street, London, UK WC1E 6BT.
Reference
1 Edsall, J. T. and Wyman, J. (1958)
Biophysical Chemistry, Academic Press
that deal with anti-inflammatory
peptides feature cytokines such as
interleukin 4 (IL-4), IL-10 and
tumour necrosis factor a, natriuretic
peptides, melanocortins, and vaso-
active intestinal polypeptide (VIP).
Among these it is the chapters on
VIP in particular that represent a
thorough overview of VIP-ergic
control of inflammation and tissue
homeostasis.
I need to record my regret, how-
ever, that the books list of peptides
that can dampen inflammatory reac-
tions is by no means complete. There
is growing evidence that somato-
statin1, galanin2, corticotropin-
releasing factor3,4 and opioid pep-
tides4,5 display anti-inflammatory
properties that can be exploited
therapeutically. Having been ex-
plored for quite some time, each of
these peptides would have deserved
a concise overview of its impli-
cations in inflammation, particularly
since the title of the volume signifies
that the known pro- and anti-inflam-
matory peptides are treated in a
comprehensive manner. However,
corticotropin-releasing factor and
opioid peptides are mentioned only in
passing, and somatostatin, galanin
and corticotropin-releasing factor are
not even referred to in the subject
index.
All in all, this book is considerably
more than merely the proceedings of
a conference. For a large part, it is a
thorough and scholarly account of
the diverse roles that peptides can
play in inflammation. The novice