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OPTION D HL: MEDICINES AND DRUGS
D 8. Drug action
D.8.1 Describe the importance of geometrical isomerism in drug action.
D.8.2. Discuss the importance of chirality in drug action.
D.8.3. Explain the importance of the beta- lactam ring action of penicillin
D.8.4 Explain the increased potency of diamorphine (heroin) compared to morphine.
This section studies the effect of some aspects of molecular structure on the action of a drug:
 Stereo-isomerism: geometric and optical isomerism.
 Strain in a 4 member ring structure.
 Polarity of a molecule.
1. Importance of geometrical (cis-trans) isomerism in drug action, e.g. cisplatin
Like in organic compounds, cis- and trans- isomerism can also occur in inorganic
transition metal complexes some of which are used in medicines. Each of the two
isomers can have its own (or lack of) pharmaceutical effects.
For instance, the compound diaminedichloro platimum (II) has a square planar
geometry with bond angles of 90 and can therefore show geometrical isomerism.
The cis-isomer shown on the right, called cisplatin, can act as an anti-cancer drug
as, because of its orientation it has both ammonia ligands on the same side and as
a result it can bond with DNA in the nucleus of cancer cells.
The trans-isomer, transplatin, does not have any pharmaceutical effects as the nitrogen atoms within the
molecule are too far apart to make bonds with the DNA in cancer cells.
2. Importance of chirality (optical isomerism) in the action of drugs
Many compounds used as medicines have chirality (the compound has two enantiomers because there is
an asymmetric atom). Natural sources of medicines (e.g. poppy) only produce one enantiomer. However,
when medicines are synthesized in laboratories often both entantiomers are produced and a racemic
mixture or racemate is obtained. A racemic mixture or racemate is an equimolar solution of both
enantiomers.
Enantiomers not only differ in the direction in which they rotate the plane of polarized light (physical
property) but they also differ in one chemical property i.e. how they interact with other chiral compounds
and this is what happens in the action of drugs as many molecules in living organisms are chiral.
To be able to recognize optical isomerism or a chiral centre in drug molecules we need to extend our
ideas of what characteristics gives molecules optical activity. We already know that a carbon atom with 4
different atoms or groups bonded onto it is a chiral centre. Carbon atoms in ring structures without
delocalization can also be chiral if one part of the ring on one side of the atom is different from the part of
the ring on the other side. Each side of the ring is classified a different group if, when moving around the
ring from the chiral centre, the order of atoms is different each way. It is said the chiral atom has two
different views around the ring.
As the case of Thalidomide proved, each enantiomer may have
completely different physiological effects. One enantiomer of
Thalidomide alleviates morning sickness in pregnant women,
while the other enantiomer causes deformities in the limbs of the
fetus.
In the diagram to the right showing the thalomide molecule,
indicate the position of the chiral carbon atom.
Other examples include:
 Ibuprofen: one enantiomer is more effective than the other.
 DOPA: this is a drug which is used in the treatment of Parkinson disease; one isomer is effective
whilst the other isomer has no physiological effect
 Fluoxetine.
 Morphine (5 chiral centres)(so has codeine): one enantiomer is analgesic;
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The effect of stereoisomerism on the development and synthesis of drugs:
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Each enantiomer must be tested for its physiological effects as its physiological effect could be
different from the other enantiomer.
Modern drugs may have only one enantiomeric form instead of a racemic mixture. This achieved by
using chiral auxiliaries – see D9.
3. Importance of the beta-lactam ring on the action of penicillin
The reactive part of the penicillin molecule is the beta-lactam ring.
The beta-lactam is a four-membered square ring structure which contains an amide group (-CONH-) and
consists of one nitrogen atom and three carbon atoms (and two hydrogen atoms).
As a result of the sp3 hybridisation of two of the three carbon atoms and the single nitrogen atom and the
sp2 hybridisation of the third carbon atom, the preferred bond angles are 109 and 120.
However, the bond angles in the beta-lactam ring structure are only 90° this puts the beta-lactam ring
structure under strain and this makes the ring structure reactive as it easily breaks open in the amide
group, for instance, in the presence of an enzyme such as transpeptidase, to form covalent bonds with
the transpeptidase. This deactivates the enzyme that synthesizes the bacterial cell walls, thus inhibiting
the growth of bacterial cell walls. As a result water enters the bacteria cell causing it to burst due to
increased osmotic pressure.
4. Importance of polarity on the action of diamorphine
Diamorphine (heroin), a derivative from morphine, is a better and more potent painkiller than morphine
and also gives a greater feeling of euphoria.
This is because diamorphine is less polar than morphine as it does not have two polar hydroxyl group
anymore as they have been replaced by two non-polar ester groups. As a result diamorphine (heroin)
cannot form any hydrogen bonds and is therefore less soluble in polar substances such as water but
more soluble in non-polar fatty tissue which makes up the central nervous system. As a result
diamorphine can cross the blood-brain barrier faster/more easily than morphine.
Lower polarity in diamorphine makes it more soluble in fatty tissue and ensure a more rapid uptake.
Increased polarity makes a medicine more soluble in water and less so in fatty tissue.
D 9. Drug design
D.9.1 Discuss the use of a compound library in drug design.
D.9.2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs
D.9.3 Describe how computers are used in drug design.
D.9.4 Discuss how the polarity of a molecule can be modified to increase its aqueous solubility and how
this facilitates its distribution around the body.
D.9.5 Describe the use of chiral auxiliaries to form the desired enantiomer.
Compound library
Compound libraries are databases that contain molecules that have been isolated or synthesized and
tested by pharmaceutical companies for possible pharmaceutical properties i.e.:
 how they inhibit or prevent normal biological activity of the ‘target’ molecule or receptor (in the case of
a pain killer)
 how they can stop or interrupt the development of a disease.
The outcome of these tests, i.e. to determine the pharmaceutical activity of the compound, and other
biologically relevant information, are also included in the compound library.
Pharmaceutical companies use such libraries to identify ‘lead’ compounds for a particular ‘target’
molecule such as an enzyme, DNA or a receptor.
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Combinatorial chemistry
Combinatorial chemistry is a technique used by pharmaceutical companies to synthesize simultaneously
(a very large number of different but structurally related compounds (all possible combinations) from a
small number of different reactant molecules by reacting them with a variety of different reagents. The
process usually results in a mixture of compounds in the same reaction vessel.
Each new compound is screened for its biological activity, resulting in a “combinatorial library”. It often
involves the mix-and-split technique using resin beads; a technique that is described below.
Parallel chemistry
Parallel synthesis involves only the synthesis of a smaller but selected group of compounds in different
reaction vessels. It involves producing a reactive intermediate bonded onto a resin bead which is then
introduced into many different vessels producing a different compound in each vessel.
Similarities between combinatorial and parallel synthesis
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Synthesis of a large number of compounds using a variety of reagents.
Uses solid-phase chemistry which also involves the mix and split technique.
Products are tested for biological activity.
Differences
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Combinatorial synthesis
Generates large, more diverse libraries “combinatorial library”.
Produces a ‘mixture’ of compounds in same
reaction vessel.
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Parallel synthesis
Small focused libraries.
Produces a ‘single’ product in each reaction
vessel.
Solid-phase chemistry
One of the techniques used in combinatorial and parallel chemistry to synthesize this large volume of
compounds is ‘solid-phase’ chemistry in which the reactions take place on the surface of resin beads:
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Each type of reactant molecule is bonded covalently onto a very small resin bead.
Mix and split process:
o The beads are mixed and then split into separate portions i.e. each portion has all reactants.
o To each portion a different reactant is added and a reaction is allowed to occur.
o The separate portions are then mixed again after which they are split into separate portion.
o To each portion a different reactant is added again…
o This is repeated.
An advantage of solid-phase chemistry: when synthesis reactions are complete, the products are
removed easily from the beads by filtering off the beads and washing them. After that the products are
tested “in vitro” and “in vivo” to find out their biological activity.
Use of computers in drug design
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Combinatorial libraries: databases used to search for molecules/groups with required/specific
properties. Databases also include 3D images of molecules
3D modeling software can be used to show interaction between medicine and active site on target
molecule/receptor without actually making the medicine. This also allows them to design molecules
with the perfect fit and then attempt to chemically produce them.
Evaluation of (biological/pharmacological) effects of new drugs; if the structure of a new molecule is
known the modeling software can then test its effectiveness in binding onto a receptor or enzyme.
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Equally, computers can be used to predict how changes to the structure of a drug might change its
activity. It can do this by 3D-modelling of the new shape or structure and use the model to find out
how it interacts with target molecule.
Making medicines more soluble in water facilitates distribution
Many medicines are either non-polar or relatively non-polar molecules. If their target area in the body is
in an aqueous environment their low solubility in water, as a result of their non-polarity, will make their
uptake slow as it will take time for the medicine, after administration, to reach its target molecule.
However, if the polarity of the medicine molecule can be improved (without altering its pharmaceutical
activity) then so can its distribution around the body and therefore its effectiveness.
In the case of non-polar molecules with either acidic (carboxylic acid) or basic (amine) groups, the
polarity can be increased by converting them into ionic salts such as chlorides or sulphates by adding
either alkalis or acids. Ionic salts dissolve in water because of the ion-dipole interactions which cause the
salt crystal to break up and the ions to disperse.
Examples are soluble aspirin and fluoxetine hydrochloride (Prozac®).
Aspirin: adding sodium hydroxide
Aspirin, which is insoluble in water and has a carboxylic acid group, can be made into an ionic salt by
reacting it with a strong alkali such sodium hydroxide to form a soluble sodium salt as shown by the
equation below:
C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COONa + H2O
The structure of aspirin in the data booklet is the structure of the insoluble aspirin. The molecule can still
act as an analgesic.
fluoxetine hydrochloride: adding an acid
In the case of fluoxetine hydrochloride (Prozac®) the structure in the data booklet is the structure of the
soluble ionic salt, hydrogen chloride salt, and this is usually the form in which it is administered or
prescribed.
Fluoxetine hydrochloride (Prozac®) is produced by reacting a
strong acid such as hydrochloric acid with the secondary amine
group in fluoxetine (see structure to the left). This reaction is
similar to the reaction between ammonia and hydrochloric acid, a
reaction you are very familiar with. In both reactions the nitrogen
atom donates its non-bonding pair to the hydrogen ion forming a
basic cation to which the chloride ion is attracted.
Use the structure above to write an equation for the formation of fluoxetine hydrochloride from fluoxetine.
Using optical isomerism in drug design: use of a chiral auxiliary
If enantiomers in a racemate have different physiological activities it is necessary to isolate the desired
enantiomer from the mixture. However, this is a wasteful process and it is therefore better to synthesize
directly the desired enantiomer by preventing the synthesis of the other enantiomer. This can be
achieved by using a chiral auxiliary.
A chiral auxiliary is an enantiomer itself and is used to convert a non-chiral reacting molecule into just one
enantiomer i.e. the enantiomer with the desired pharmaceutical effect. It does that by attaching itself to
the non-chiral molecule to create the stereochemical conditions necessary to force the reaction to follow
a certain path i.e. the production of the desired enantiomer and not the other enantiomer.
Once the new desired molecule has been formed, the auxiliary can be taken off and recycled.
A product of this type of synthesis is Taxol, an anti-cancer drug.
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D 10. Mind-altering drugs
D 10.1 Describe the effects of lysergic acid diethylamide (LSD), mescaline, psilocybin and
tetrahydrocannabinol (THC).
D 10.2 Discuss the structural similarities and differences between LSD, mescaline and psilocybin.
D 10.3 Discuss the arguments for and against the legalization of cannabis.
Examples of mind-altering drugs: lysergic acid diethylamide (LSD), mescaline, psilocybin and
tetrahydrocannabinol (THC) which is found in cannabis.
Short term effects of lysergic acid diethylamide (LSD), mescaline, psilocybin
All three cause hallucinations i.e. hearing of voices and seeing of images which appear realistic but which
do not exist i.e. there is no stimulus for them. The mind-altering drugs disrupt the activity of the brain
transmitter serotonin that is involved in the processing of hearing and sight.
In addition, each hallucinogenic also causes their own effects.
lysergic acid diethylamide
(LSD),
 Psychological dependence
 Effects of LSD may be
experienced a year or more
later after last use i.e.
“flashbacks”
mescaline
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Nausea
Trembling
Liver damage
Reduced appetite
psilocybin
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Feelings of relaxation
Develop tolerance
Sense of well-being
Similarities and differences in the structures of LSD, mescaline and psilocybin
similarities
differences
 benzene ring
 amine group(s)
LSD
 indole ring = a benzene ring to which is attached (fused) a fivemembered ring with a nitrogen atom and a double carbon-carbon bond
(see data booklet table 20)
 amide
 2 alkene - double bonds
 2 amine groups: a secondary amine and a tertiary amine
mescaline  no indole ring
 primary amine
 ether (- 3 groups)
psilocybin  indole ring
 secondary amine
 has an ionic end/tertiary amine ion
 a phosphate group
Effect of cannabis
The active ingredient in cannabis is tetrahydrocannabinol (THC) and this has the following effects:
 loss of sense of time
 confusion
 light-headedness
 sense of floating
 loss of inhibitions
 euphoria
 mental relaxation
Structure of cannabis
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Phenol group, ether and a double carbon-carbon bond.
Legalization of cannabis
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for
no more or less damaging than other ‘legal’
drugs e.g. alcohol, tobacco
offers pain relief from certain diseases such as
AIDS and cancer
relieves nausea in chemotherapy
relieves tension and anxiety in terminally ill
patients
helps decrease pressure inside eyeball in
patients suffering from glaucoma
better control of quality of cannabis
reduction of crime
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against
harmful effects:
o may suppress immune system
o respiratory ailments
reduces ability to drive
causes dependence
the possibility of cannabis users moving on to
harder drugs.
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