Table Of ContentPROGRESS IN DRUG RESEARCH
FORTSCHRITIE DER ARZNEIMITIELFORSCHUNG
PROGRES DES RECHERCHES PHARMACEUTIQUES
Vol. 20
Progress in Drug Research
Fortschritteder Arzneimittelforschung
Progres des recherches phannaceutiques
Vol. 20
Edited by . Herausgegeben von· Redige par
ERNST JUCKER, Basel
Authors· Autoren . Auteurs
A. BURGER, R.P. AHLQUIST~ S. ARCHER and W.F. MICHNE, E.J. ARIiiNS,
P.A. LEHMANN and J.F. RODRIGUES DE MIRANDA, B. BERDE, c.J. CAVALLlTO,
G. DESTEVENS, G. DESTEVENS and M. WILHELM, W. DORST, A.F. BOTTSE
and G.M. WILLEMS, D.R.H. GOURLEY, P.A.J. JANSSEN, A. MARXER
and O. SCIDER, M.J. MILLER, J.A. MONTGOMERY, TH. STRULLER,
M. VON ARDENNE, W.J. WECHTER and B.E. LOUGHMAN
1976 Birkhauser Verlag Basel
und Stuttgart
© Birkhauser Verlag, Basel, 1976
Softcoverreprintof the hardcover 1st edition 1976
ISBN-13:978-3-0348-7096-2 e-ISBN-13:978-3-0348-7094-8
DOl: 10.1007/978-3-0348-7094-8
Foreword
Volumes 18 and 19 of "Progress in Drug Research" differed from the earlier
volumes insofar as they were concerned almost exclusively with problems in
the field of Tropical Medicine. The editor and publishers believed that in this
way some contribution could be made to the solution of some of the many
problems with which the developing countries are burdened. The 20th
volume, however, is in the customary form; it contains 17 contributions from
various areas of drug research and therapy. Whereas the articles concentrate
on a short representation of the progress which has already been made,
nevertheless reference is also made to the many unsolved problems within the
particular areas. The editor hopes that the 20th volume will not only represent
a comprehensive review but will also be of some use in focusing further
investigations on problems of medicine that have still not been overcome.
The editor would also like to take this opportunity of expressing his gratitude
to Dr. A. Naffor carefully working over the manuscripts and correcting proofs.
Thanks are also due to the publishers and the printers, Druckerei Birkhauser,
especially Dr. A. Birkhauser, Th. Birkhauser and C. Einsele, for their painstaking
work on the printing and lay-out of the volume.
August 1976 Dr. E. JUCKER
Sandoz AG, Basel
Vorwort
Die Bande 18 und 19 der «Fortschritte der Arzneimitte1forschung» wichen
insofern von den vorhergehenden Banden ab, a1s sie fast ausschliess1ich
Prob1eme der Tropenkninkheiten behandelten. Herausgeber und Verlag
waren der Ansicht, damit einen Beitrag zur Losung einiger der vie1en, die
Entwick1ungs1ander bedrangenden Prob1eme zu 1eisten. Der 20. Band ist
wieder nach dem iiblichen Schema aufgebaut; er enthalt 17 Beitrage aus
verschiedenen Gebieten der Arzneimittelforschung und der Therapie, wobei
das Schwergewicht auf einer kurzen Darstellung des bisher Erreichten liegt,
jedoch auch auf die vie1en unge10sten Prob1eme innerha1b der einzelnen
Gebiete hingewiesen wird. Der Herausgeber hofft, dass der 20. Band nicht nur
a1s Vermittler einer umfassenden Ubersicht, sondern auch als Instrument zur
Ausrichtung zukiinftiger Forschungen aufnoch nicht bewaltigte Prob1eme der
Medizin von Nutzen sein kann.
Herrn Dr. A. Naf mochte der Herausgeberauch an dieser Stelle flir die
sorgfaltige Uberarbeitung der Manuskripte und die Korrektur der Fahnenab
ziige den besten Dank aussprechen. Dem Verlag und der Druckerei Birkhau
ser, besonders den Herren Dr. A. Birkhauser, Th. Birkhauser und C. Einse1e,
gebiihrt Dank flir die sorgfaltige Druck1egung und gute Ausstattung des
Bandes.
1m August 1976 Dr. E. JUCKER
Sandoz AG, Basel
Contents . Inhalt . Sommaire . VoL 20
The State of Medicinal Science ................................... 9
By Prof. Dr. A. BURGER
Adrenergic Beta-Blocking Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27
By Prof. Dr. R. P. AHLQUIST
Recent Progress in Research on Narcotic Antagonists . . . . . . . . . . . . . . . .. 45
By Prof. Dr. S. ARCHER and Dr. W.F. MICHNE
Stereoselectivity and Affinity in Molecular Pharmacology . . . . . . . . . . . . .. 10 1
By Prof. Dr. E.J. ARI£NS, Dr. P.A. LEHMANN and Dr. J. F. RODRIGUES DE
MIRANDA
Industrial Research in the Quest for New Medicines .................. 143
By Dr. B. BERDE
Changing Inflnences on Goals and Incentives in Drug Research and
Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 159
By Dr. c.J. CAVALLITO
The Interface between Drug Research, Marketing, Management, and
Social, Political and Regulatory Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 181
By Dr. G. DESTEVENS
Antihypertensive Agents ......................................... 197
By Dr. G. DESTEVENS and Dr. M. WILHELM
Transport and Accumulation in Biological Cell Systems Interacting with
Drugs ......................................................... 261
By Dr. W. DORST, Dr. A.F. BOTTSE and Dr. G.M. WILLEMS
Isolation and Characterization of Membrane Drug Receptors . . . . . . . . . . . 323
By Prof. Dr. D.R.H. GOURLEY .
The Levamisole Story ........................................... 347
By Dr. P.A.J. JANSSEN
Fundamental Structures in Drug Research .......................... 385
By Prof. Dr. A. MARXER and Dr. O. SCHIER
Protozoan and Helminth Parasites - A Review of Current Treatment. . . . . 433
By Prof. Dr. M.J. MILLER
The Current Status of Cancer Chemotherapy ........................ 465
By Dr. J.A. MONTGOMERY
Problems of Medical Practice and of Medical-Pharmaceutical Research .. 491
By Dr. TH. STRULLER
8 ContentS· Inhalt . So=aire . Vol. 20
Cell-Kinetic and Pharmacokinetic Aspects in the Use and Further Devel-
opment of Cancerostatic Drugs .................................. " 521
By Prof. Dr. M. VON ARDENNE
Where Is Immunology Taking Us? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 573
By Dr. W.J. WECHTER and Dr. BARBARA E. LOUGHMAN
Index, Vol. 20 ................................................... 593
Subject Index· Sachverzeichnis· Table des matieres, Vol. 1-20 ......... 604
Author and Paper Index· Autoren-und Artikelindex . Index des auteurs et
des articles, Vol. 1-20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 610
9
The State of Medicinal Science
By ALFRED BURG:aR
Professor Emeritus, University of Virginia, Charlottesville, Virginia 22901, USA
Medicinal science involves the study of pharmaca, especially of chemicals
used in medicine as therapeutic and occasionally as prophylactic agents. It is
based on combinations of experimental biology and chemistry and physics
applied to the understanding of pathologies and restoring normal conditions
in animal cells and tissues. The widest areas contributing to medicinal science
are medicinal chemistry, biochemistry and pathology applied to metabolic
aberrations, pharmacology, microbiology and virology, endocrinology and
immunology. Many medical specialties funnel information into medicinal
science and vice versa where pharmacotherapeutic treatment is involved. It
would be a great advantage if unified concepts could be found to tie all these
activities together. In physics and chemistry, the trend toward such generaliza
tions is making progress. Biology and behavioral sciences are approaching the
stage at which many of their phenomena are becoming classifiable as chemical
and physical manifestations. But unified explanations in biology run into
difficulties through refined visual observations and instrumental measure
ments. As we advance toward visualization of macromolecules by electron
microscopy, X-ray diffractometry and other spectroscopic methods, we witness
a centrifugal expansion of what had been thought to be ultimate biological
entities only a few years ago. Where 'animate' matter and macromolecules
meet we recognize the growing importance of molecular aggregation and
polymerization. This forces us to accept subunits as models for the aggregates
which are chemically too complex to be handled with present means. Never
theless, we are advancing gradually from manageable molecules to as yet
unmanageable biostructures. We believe that conformational changes in
flexible molecules are pristine manifestations of motion, and that there is a
steady transition between these changes and motion associated with biological
behavior. Likewise, chemical reactivity based on the spin of electrons must be
a fundamental phenomenon of macrobiological and behavioral reactions as
we observe them in our environment. The postulated continuity of such events
cannot yet be proven, and our beliefs remain rungs in a ladder of natural
philosophy that explains for the moment what we know, and serves as a
working hypothesis for the next step toward increasing complexity. Because
methodology has changed much more rapidly in the last 25 years than in the
whole previous history of science, our day-to-day natural philosophies have
been in constant and - to the non-expert - bewildering flux.
10 A. Burger
Into this milieu of changing interpretations of biomolecular observations steps
the medicinal scientist, inserting small foreign molecules into the cogs of
cellular machinery that he does not yet understand, and drawing conclusions
from the effects of his arbitrary intrusions. Gross pharmacological observa
tions such as vascular tone, pain perception, electrical discharges of neurons,
rates of cardiac or respiratory activity, etc., do not give us much insight into
underlying biochemical phenomena. In studies on this level, we must explain
the results of our medicinal manipUlations at the lowest end of the ensuing
events, that is, the changes and reactions that occur to a foreign molecule in
the biological environment. If we are lucky, we can record some readily
measurable biochemical change that can be traced to the action of the artifact
we have used. We can observe whether the tissues - and now we are dealing
with incredibly complex structures beyond fundamental comprehension - are
benefited or damaged by our artifact. Beyond these scientific observations lie
value judgments by applied scientists such as physicians, and by philosophers
trying to superimpose their opinions on medical rationale.
This pattern of medicinal research by shadow-boxing in which we try to hit
with a pharmacon something we cannot see clearly, had been established by
the 1950's. It is mirrored in many pioneering articles in Progress in Drug
Research since the appearance of the first volume in 1959. What has changed
during the last 10-15 years is drug development for clinical investigation and
the clinical study itself [1]. This will be discussed later. The transition from
non-correlated to mission-oriented preclinical research shall be explored first
to lead us up to today's accepted methodology.
Early examples of classical empirical patterns of drug discovery are seen in the
work that led from natural 'lead' compounds to synthetic improved drugs, as
from cocaine to ester and amide local anesthetics [2], from quinine to mefio
quine, quinacrine, chloroquine and primaquine [3], or epinephrine and other
natural adrenergic amines [4] via ephedrine [5] and amphetamine [6] to more
specific 01:- and ,8-adrenergic agonists and antagonists [7]. Natural products
gave way to synthetic 'leads' in the early chemotherapeutic studies of PAUL
EHRLICH'S [8] and their echo in DOMAGK'S in vivo antibacterial azo dyestuffs [9].
The discovery of sulfanilamide as the active metabolite of these dyestuffs [10]
was a foregone conclusion from Ehrlich's comprehensive and prophetic ideas
about metabolic activation as a mechanism of drug action.
The structural modification of the early sulfanilamides, carried out on a vast
scale, illustrates the concern with another possibility of drug discovery,
namely, through the observation of side effects which can give rise to pharma
cologically entirely different drugs in other fields of therapy. These manipula
tions provided entries to oral hypoglycemic agents, antihypertensive and
diuretic drugs, antigout agents, antithyroid drugs and antileprotic diaryl
sulfones [11].
The evaluation of side effects has put the onus on pharmacologists to discover
new leads during experimental and clinical studies of existing drugs. In most
cases such discoveries are made only after a drug has been introduced into
Medicinal Science 11
medical practice, largely because enough drug and enough clinical cases are
available to confirm incidental observations of alternate activities. This has
alerted pharmacologists to look for potentially useful side actions during
animal test studies although confirmation in the clinic eliminates the possibility
of species specific activities brought about by differences in drug metabolism.
The antagonism of sulfanilamide and p-aminobenzoic acid opened the door to
the intellectually stimulating search for new drug structures among structural
analogs of small biochemicals, especially biosynthetic intermediates and end
products. The value of this approach for the discovery of practical, clinically
useful drugs will be examined later. For the moment, the method requires
structural modification of the 'lead' compound, that is, the biochemical
prototype. Since the same rules govern the molecular modification of any
'lead' compound, they shall be mentioned here briefly.
Molecular modification funnels analogs of biologically interesting prototype
compounds into screening programs. Of course, screening can utilize com
pounds 'off the shelf' and this procedure has unearthed numerous valuable
candidate drugs. When a structure shows notable biological activity in a
screening test, one chooses it as a 'lead' for derivatives and analogs. Some
'leads' arise from a search among natural products whose botanical sources
are endowed with therapeutic folklore, others from the intelligent interpreta
tion of natural metabolites as causative factors in disease. Regardless of the
nature of the source of a prototype compound, molecular modification
continues the process of selection of the most effective and in every case, the
least generally toxic compounds in a given series. Almost all major synthetic
and partially synthetic drugs have been found in this way, and the phar
maceutical industry has not yet devised a better method of singling out
optimal agents in a given test procedure.
Before 1930 molecular modification consisted of systematic variation of
homologous or analogous substituents and functional groups, cross-overs into
chemically related systems and similar devices that would readily suggest
themselves to an organic chemist. There was usually no good reason for doing
all this except the desire to do the most obvious alterations first. Operations
were chosen on the basis of synthetic expediency and only rarely for other
reasons. There were occasional visions of biochemical insight as in Ehrlich and
Bertheim's systematic studies of aromatic arsenicals, the SCHONHOFER qui
none (tautomerism) hypothesis [12] for aminoquinoline antimalarials and the
NENCKI salol principle [13]. But most work was dictated by organic chemical
considerations only; it was unimaginative, boring and wasteful. More sophisti
cated organic chemists regarded it as an inferior exercise, and the dismal early
academic and industrial laboratories of pharmaceutical chemistry bore wit
ness to this low degree of esteem. Collaboration with experimental biologists
was minimal on the whole and even where it existed the cross-over of sugges
tions for the direction of further researches was rare. The highly pertinent
hypotheses of OVERTON [14] and MEYER [15] concerning biological transport
mechanisms remained of academic interest.
