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Book Review Medicinal Chemistry. The Role of Organic Chemistry in Drug Research. Edited by C. R. Ganellin and S. M. Roberts

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BOOKS
An Overall Picture of Biomembranes from the Mosaic of Data
Biomembranes. Physical Aspects.
Edited by M . Shimitzky. VCH Verlagsgesellschaft,
Weinheim/VCH
Publishers, New York, 1993. 371 pp.,
hardcover DM 198.00, $ 135.00.ISBN 3-527-30021-X/l-56081-771-2
This book is the first volume in a series
that aims to provide a structure for the
many-faceted subject of biological membranes; it is concerned with the physical
phenomena that result from the integrity
and fluidity of lipid double layers. This is
a well-chosen topic to begin the series, as
it introduces the basic principles for later
discussions of membrane functions.
Although the present picture of lipid
membrane structures is fairly clear, it is a
mosaic made up of many thousands of
publications. Does this book fulfill its
claim to provide the picture with a structure‘? I n my view it mainly does; three of
the chapters achieve this especially well,
and these will be described first. In Chapter 4 on “Fluidity, Dynamics, Order”, B.
Wieb van der Meer defines in a brief and
simple way six types of dynamic processes
in lipid membranes. then treats these in a
textbook style, comparing and evaluating
their importance. Molecular alignment,
domain formation, and asymmetry in
membranes are thoroughly discussed, as
also are basic concepts. methods, and current problems. The bibliography to this
chapter is systematically arranged and includes full titles. enabling the reader to
quickly find material on topics of particular interest. Chapter 7 on the electrical
properties of membranes (L. M. Loew) is
much shorter, but this too strikes me as
perfect in its way. Here again one finds an
easily readable text, with illustrations that
are precisely in harmony with it, and the
I
This section contains hook reviews and a list of
nen hook:, received by theeditor. Book reviews are
written by invitation from the editor. Suggestions
for hooks to be reviewed and for book reviewers
are welcome. Publishers should send brochures or
(better) books to Dr. Ralf Baumann. Redaktion
Angewandte Chemie. Postfach 101 161. D-69451
Weinheini. Federdl Republic of Germany. The editor reserves the right of selecting which books will
bc rtbiewed. Uninvited books not chosen for
revim will not hc returncd.
titles of the most important publications
are given. Also very pleasing is Chapter 6,
in which Y I. Henis gives a detailed description, with up-to-date illustrations, of
the interesting method of “fluorescence
photobleaching recovery”.
On the other hand, the remaining four
chapters are competently written surveys
of particular topic areas, rather than attempts at providing a structure. In Chapter 1 D. Marsh summarizes the thermodynamic equations from the more extensive
treatment in his book Phospholipid Biluyers, but a clear physical model fails to
emerge from the illustrations or from the
qualitative descriptions of the forces that
are at work. Chapter 2. by D . Chapman,
is concerned with phase transformations
in lamellar, hexagonal, and cubic phases.
In my view this does not really fit into the
subject of biomembranes. despite the inclusion of a section entitled “Biological
Relevance” which introduces comparisons with cell partitioning, domain formation, etc. The same comment applies to
the topic of micelles in Chapter 3 by D.
Lichtenberg. since to my knowledge micelles in the usual sense do not occur in
biological systems. In contrast liposomes
are not treated in sufficient detail. There
are no electron micrographs of these. nor
is there anything on fusion models or undulations. Most of the figures are more
likely to mislead than to elucidate the text
(examples: Figs. 8 and 9 show micelles
that are not curved, which is very untypical; Fig. 4 shows turbidity occurring as a
result of micelle formation, despite the
fact that micellar solutions are nearly always quite clear; Fig. 2 shows molecular
models that are cone-shaped, even though
there are no examples of these). That
leaves only Chapter 5 on lipid-protein interactions, by A. H. Parola, which is by
far the longest in the book. I feel that the
content of this chapter is well summarized
by the author’s comment on page 221 that
“...work on membrane protein purification and reconstitution leaves very limited
evidence of specific lipid requirements for
membrane protein reactivation ...”. The
listing of the many proteins whose interactions with liposomes have been investigated makes boring reading for the nonspecialist, and the discussion of the results
yields few surprises. On the other hand, a
novel idea that could be important is the
model of malignant plasma membranes
with intercalated domains of electroneutral lipids (also containing DNA?-this
point is not made clear). The comprehensive survey of protein- lipid interactions
is, of course, of central interest to the specialist reader.
The book is undoubtedly an important
addition to the literature for the reader
envisaged in the preface, who is engaged
in research in this field. He or she will find
here comprehensive information on membrane fluidity, membrane proteins, and
electrical properties. However, this thorough coverage extends only up to 1988;
beyond that it becomes thin. For the students also envisaged as potential users, I
recommend Chapters 4, 6, and 7 as readable introductions; they will also find
Chapter 5 useful, although much of it can
be skipped over. With regard to the introductory Chapters 1 -3, the student
would be better served by other books,
such as Phospholipid Bi1qvr.c. by G . Cevc
and D. Marsh, Menibrune Mimetic Cliertiistry, by J. H. Fendler. and Iii~ermolcculur
and Surfuce Forces. by J. N. Israelachvili.
It is not until Chapter4 when the focus
turns to biological aspects that the book
begins to fulfill its special objective. One
must therefore hope for the best in the
volumes that are to follow.
Jiirgetl-H. FUhi‘ll(p
Institut fur Organische Chemie
der Freien Universitiit Berlin (FRG)
Medicinal Chemistry. The Role of Organic Chemistry in Drug Research.
Edited by C. R. Ganellin and S. M .
Roberts. Academic Press, London,
1993. 302 pp., hardcover E 29.00.ISBN 0-12-274120-X
Eight years after the publication of the
first edition of this book, this new edition
has appeared. It consists of 14 chapters
with 17 authors, offering the reader an excellent survey of the pharmacological aspects and the synthesis, development, and
medical importance of new pharmaceutical
products. The descriptions of pharmacologically active compounds and their meth-
BOOKS
ods of preparation are illustrated throughout by structural formula diagrams.
Seven of the chapters are revised and updated treatments of topics that were included in the first edition, and these appear at
the beginning and end of the new version,
as follows: Chapter 1. “Introduction to
Receptors and the Action of Drugs”;
Chapter 2. “Structure and Catalytic Properties of Enzymes”; Chapter 3. “Receptor
Pharmacology”; Chapter 10, “Beta Blockers”: Chapter 11, “Salbutamol: A Selective P2-Stimulant Bronchodilator”; Chapter 12, “Discovery of Cimetidine, Ranitidine and other H,-Receptor Histamine
Antagonists”; Chapter 14. “Clavulanic
Acid and Related Compounds: Inhibitors
of P-Lactamase Enzymes”. The new chapters that have been added are: Chapter 4,
“Drug Access and Prodrugs”; Chapter 5.
“QSAR and the Role of Computers in
Drug Design”; Chapter 6. “The Current
Status and Future Impact of Molecular
Biology in Drug Discovery”; Chapter 7,
“General Approaches to Discovering
New Drugs: A Historical Perspective”;
Chapter 8, “Discovery and Development
of Cromakalim and Related Potassium
Channel Activators”; Chapter 9, “Angiotensin-Converting Enzyme (ACE) Inhibitors and the Design of Cilanapril”;
Chapter 13, “Fluconazol. an Orally Active Antifungal Agent”.
Following the introduction to the general principles of pharmacology in the first
half of the book, the emphasis in the second half is on the practical importance of
pharmaceutical compounds in areas where
there is likely to be impressive progress in
the age of our modern industrial society.
Chapter 8 describes a new therapeutic
principle for the treatment of cardiac and
circulatory disorders and bronchial asthma, which is becoming increasingly important with the discovery of the mechanism whereby cromakalini acts as a potassium channel activator. Chapter 9 is concerned with ACE inhibitors, which are now
the most favored agents for the treatment
of hypertension and cardiac degeneration.
The development of ACE inhibitors such
as captopril, enalapril, and cilazapril is described, together with their biological
properties. Chapter 10 discusses the chemistry, pharmacology. and clinical effects of
beta blockers, which competitively and reversibly inhibit the positive inotropic and
chronotropic effects of catecholamines on
the heart (by blocking the P, receptors),
and also inhibit bronchospasmolysis by
blocking the p, receptors. Chapter 11 is
concerned with salbutamol and analogous
compounds derived from adrenalin and
isoprenalin, which are used in the treatment of bronchial asthma. Chapter 12 is
devoted to cimetidine and ranitidine. two
compounds that rank as milestones in the
development of H,-receptor histamine antagonists and are used in the treatment of
gastritis and ulcers; their preparation is
described in detail and structureeactivity
relationships are discussed. Chapters 13
and 14 are concerned with antiinfectives,
in particular with the widely used orally
active antifungal agent fluconazol and with
clavulanic acid which is used as an inhibitor of p-lactamase enzymes. A combination of clavulanic acid with amoxicillin
has proved successful as a further development in the penicillins field.
This altogether excellent book, an enlarged revision of the edition published in
1985, is a valuable addition to other recently published books on medicinal chemistry (R. B. Silverman, Tj7e Organic Clzetnistry qf’ Drug Design and Drug Action; B.
Testa, W. Fuhrer, E. Kyburz, and R. Giger,
Perspectives it1 Medicinal Chrmistrj~;both
published in 1992). Medicinal Chernistrj.
contains many valuable articles which help
the reader to understand important concepts of pharmacology and molecular biology, and describe new developments in
pharmacological agents.
Gunter Schrnidt
Bayer AG
Wuppertal (FRG)
2D NMR. Density Matrix and Product Operator Treatment. By G. D.
Muteescu and A . Vuleriu. PTR Prentice Hall, Englewood Cliffs, 1993.
200 pp., hardcover $ 50.00.--ISBN
0-1 3-013368-X
This book aims to provide the reader
with a detailed guide to analyzing multiplepulse N M R experiments, using the density
matrix and product operator approaches.
The text is deliberately and unashamedly
didactic in its approach, and the calculations are set out step-by-step without leaving out any intermediate results. In addition, the manipulations by which a result
is simplified and interpreted are also set
out in some detail.
The first section of the book is devoted
to examples of the use of the density matrix approach, the first such example being an analysis of the HETCOR experiment whereby one observes 13C and obtains a two-dimensional I3C- ‘H shift
correlation spectrum. The authors introduce the concept of the density matrix.
explaining how to set up the equilibrium
conditions, the effect of pulses, how to
calculate evolution. and finally how to
calculate observables. Each of these ideas
is introduced as it is needed in deducing
the effect of the pulse sequence. and so
there is a natural flow to the discussion.
with the concepts appearing in context.
Having completed the analysis. the authors then compare this with an attempt
at a vector analysis of the sequence, showing that the vector method is at best
cumbersome. and at its worst extremely
confusing. The reader is left with the impression that multiplying matrices together is preferable to trying to understand the apparently random rules that
govern these vectors.
The main criticism of this opening section is that it rather fudges the important
issue of the connection between the terms
one sees at the end of a calculation and the
appearance of a two-dimensional spectrum. The authors do not make a clear
distinction between terms which simply
affect the amplitude or phase of a peak
and those which contain the information
about the frequencies present in the F ,
spectrum. Further, the connection between the form of these terms and the
phase (or even sign) of the peaks in the
spectrum is not well described.
The density matrix section goes on to
cover the INADEQUATE and COSY
procedures. As before. the issues of phase
and lineshapes are somewhat lost, and the
difference between the phase properties of
the cross and diagonal peaks in COSY
spectra receives scant attention. The section closes with a discussion of “phase cycling” in the COSY experiment; in fact
the topic covered is frequency discrimination. which is rather a different matter.
The second section of the book goes on
to introduce the product operator formalism, again using the approach of showing
how a calculation is done and highlighting
the rules by which these operators are manipulated. Some time is spend on establishing the relationship between the operators, their matrix representations, and
observable signals; this is a welcome discussion. Once again HETCOR is used as
the first example but, incredibly, this is the
only two-dimensional experiment analyzed
using product operators. The remainder
of the examples are all one-dimensional
experiments, such as DEPT; in these cases
the analysis is extended to include magnetic equivalence. It is very unfortunate
that the authors did not include COSY
and double-quantum-filtered COSY as examples, as these both provide excellent
vehicles for explaining the usefulness and
properties of product operators. Generally
speaking, this section on product operators does not read well; the overall impression is one of confusion, and a lack of
structure and authority.
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