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THE RELATION BETWEEN CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY - J Pharm Pharmacol, 1963, 15(1), 285-316 - j.2042-7158.1963.tb12787.x.

THE RELATION BETWEEN CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY - J Pharm Pharmacol, 1963, 15(1), 285-316 - j.2042-7158.1963.tb12787.x.

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Published by Jonathan Berry
THE RELATION BETWEEN CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY - J Pharm Pharmacol, 1963, 15(1), 285-316 - j.2042-7158.1963.tb12787.x.
THE RELATION BETWEEN CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY - J Pharm Pharmacol, 1963, 15(1), 285-316 - j.2042-7158.1963.tb12787.x.

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Published by: Jonathan Berry on Jan 03, 2013
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REVIEW
ARTICLE
THE
RELATION BETWEEN CHEMICAL STRUCTURE
AND
BIOLOGICAL ACTIVITY*
DISCUSSION
F
POSSIBILITIES, PITFALLS AND
LIMITATIONS
BY
J.
M.
VAN
Rossm,
Ph.D.
Department
of
Pharmacology, Catholic University of Nijmegen, the Netherlands
THEnumber of new compounds being synthesised every year increases inan exponential way. Consequently investigations of the relation betweenchemical structure and biological activity similarly increases. Studies
of
this kind provide information about which moieties in the moleculeare essential to obtain potent and specific drugs. Furthermore they maygive a clue to the mechanism
of
the action of drugs.Two major aspects
of
structure-activity studies raise questions. Firstly,how do alterations in the chemical structure alter the geometry
of
themolecule and its physical properties? Secondly, what does the fact ofbiological activity imply? Do different drugs produce the same kind ofeffect
;
do they have an identical mechanism
of
action?In this review the value of studies on structure-activity, as well as someof the pitfalls and limitations of interpretation will be discussed. Workdone on the pharmacology
of
the nervous system will be used to illustratethis discussion.
ACTION
ND
ACTIVITY
Investigations of structure activity relationships will be abbreviated to
SAR
studies. This notation is vague because it is also frequently used forstructure action relationship studies.The action, or effect, of
a
drug is
a
qualitative phenomenon while
its
activity is
a
quantitative measure denoting how much effect is produced.When the activity
of
a series
of
drugs is compared, as in
SAR
studies, it isessential that all members of the series cause the identical effect
;
and notonly the same effect, but they also should have an identical mechanism ofaction. In many examples this is not
so.
Different drugs
may
produce a similar effect by an entirely differentmechanism of action. For instance, the blood pressure may be loweredby acetylcholine as a result of vasodilatation of arterioles, but also byhistamine when large numbers of capillaries are themselves dilated. It isevident that when the observed effect is achieved by a complicated function,many drugs produce similar effects by acting in different ways while, onthe other hand,
a
single drug may produce a divergency of actions.This is
so
with drugs acting in the intact animal and especially when theyact on the central nervous system. The study of drugs on isolated organsmakes things less complicated but
it
is not always possible to extrapolate
in
vim
findings to intact animals or to man.
*
Based on a lecture given
for
the pharmacological day during the
XXII
Inter-national Congress
of
Physiological Sciences, Leiden,
on
September
18,
1962.
285
 
J.
M.
AN
ROSSUM
Therefore to reduce variables to a minimum the activity must bemeasured in unambiguous terms. Some knowledge of molecular pharma-cology seems necessary for this purpose.
80-160
0.t-I0
Interaction with Receptors
Most drugs are supposed to interact with receptive sites or receptorsin the tissue. The molecular structure of the receptor and its physicaland chemical properties largely determine what moieties
in
the drug areessential for affinity with the receptors. Other factors however also playa role.Some receptors have strong structural requirements and therefore seemto be rather rigid, whereas others are very much less
so.
Thus the sitesof activity of the volatile anaesthetics are hardly to be called receptors.The potency of these drugs depends largely on their being in the tissuefluid where chlartrate formation (Pauling, 1961) may occur,
so
that theelectrical impedance of the tissue increases and conduction is impaired.Ferguson
(1
930) has calculated the activity, that is, the effective concentra-tion, of volatile anaesthetics at their locus of action and was able to showthat they differed little in potency. The geometric structure seems oflittle importance and there is not a great difference in potency betweendiastereoisomers and enantiomorphs.
40-
80
1-2
5-10.
0.1-
0s
TABLE
I
SAR
ON
SPECIFIC
AND
NONSPECIFIC
RECEPTORS,
ACTIVITY
ESTIMATED
ON
THE
GUINEA-PIG
ILEUM
-0aii-C
I
-H
-C-C-<
0
-H
c-c'
-d
I
Other types of drug action involve a requirement for highly structuralreceptors as, for instance, parasympathetic receptors or histamine recep-tors. Examples are set out in Table
I
(Stelt, Harms and Nauta,
1961).
From this Table it may be seen that changes in the molecular structuremay cause the potency of the antihistamine or antiacetylcholine drug toincrease sharply, whereas spasmolytic (papaverine-like) drugs acting on
286
 
CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY
the muscle directly, seem hardly to be influenced. The papaverine-likeeffects seem to depend on non-specific receptors. For drugs acting oninflexible receptors there may be a great difference in the activity of optical
TABLE
I1
DIFFERENCE
N AFFINITY
OF
OPTICAL
ISOMERS
drug
and
(class)
chlorphenimmine
(antihbhninio)
hyoscymnine(p.sympatholytic)levorphan(analgesic)
no-
drenuline
(OrL~pthomim)
isoprenaline
bB-srm@om~.)
nicotine
(gcmslicol
stimulant
isomers. See Table
I1
(Ariens,
1962;
Barlow,
1960;
Beckett,
1959;
Hanna,
1960;
Kroneberg,
1955;
Luduena,
1957, 1962;
Schild,
1947).
BASIC
STEPS
N
DRUG
ACTION
Since drugs are chemical substances an interactiog of drug moleculeswith specific receptive molecules (receptors) in the biological tissue is anessential part in almost any form of drug action. For receptor occupa-tion
a
sufficient number of drug molecules should be in the direct vicinity
of
the receptors. This environment has been called the biophase (Furch-gott,
1955).
TheJirst
basic
step
in drug action is therefore to discoverhow drug molecules reach the biophase and thus to build up an adequateconcentration after administering the drug.It is obvious that thisrelation depends on the dose, the route of administration, on where thereceptors are located in the tissue
(on
the exterior surface of the cell, orinside it, or in the brain) and
on
the biotransformation by enzymes.
In
intact animals, and especially when drugs are acting in the brain, therelationship between the dose applied and the concentration in the bio-phase may be very complicated.Furthermore, the concentration in the
281

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