D.8 Drug action
D.8.1 Describe the importance of
geometrical isomerism in drug action.
Stereoisomers are compounds with the same molecular and structural
formula, but a different arrangement of atoms in space. Geometric isomers are a
type of stereoisomers. In general, geometric isomers occur in species with a
bond with restricted rotation. However, in some geometric isomers, when there
are different atoms bonded to the same molecule, like in cisplatin, the
phenomenon may occur.
The trans- and the cis- form of a drug can exhibit different
properties. One geometric isomer may have the desired pharmacological effect,
while the other may be less effective or have adverse side effects.
Example: Cisplatin is a drug used to treat testicular and ovarian
cancer. The medicine exhibits geometric isomerism. However, only the cis- form
of the drug is effective—the trans- form has no effects whatsoever. Only
cisplatin can react with two guanine molecules in the DNA. Remember that
cisplatin is square planar!
Cisplatin Transplatin
D.8.2 Discuss the importance of
chirality in drug action.
Optical isomers are stereoisomers chiral, or asymmetric, around one of
the atoms. Body is a very precise machine, so the chemicals inside often exist
as one of the enantiomers.
Only one enantiomer of drugs exhibiting optical isomerism sometimes has
the desired pharmacologic effect. The other enantiomer may have weaker effect
or severe adverse side effects. The pharmaceutical companies are likely to
manufacture only the desired enantiomer because producing the ineffective
enantiomer is financially inefficient, or to avoid the adverse effects of the
harmful enantiomer.
The atom around which a molecule is chiral has four different atoms
attached to it! Do not confuse optical isomerism with geo-isomerism!
Example: Thalidomide – one enantiomer alleviates symptoms of the
pregnancy morning sickness, the other enantiomer causes deformities in the
limbs of fetus
Ibuprofen - one enantiomer is effective, while the other is not
Naproxen – one enantiomer is a pain
reliever, the other one is a liver toxin
Other examples include amphetamine
and taxol. We use asterisk (*) to denote the chiral atom.
D.8.3 Explain the importance of the beta-lactam ring
action of penicillin.
The beta-lactam ring has an unusual square structure, where each bond
is 90̊. Due to its irregularity, the beta lactam ring is very reactive. The
ring opens and covalently bonds to the enzyme transpeptidase, responsible for
the forming of bacterial cell walls. If bacterium is unable to build its cell
wall, it bursts, disintegrates and dies.
D.8.4 Explain the increased
potency of diamorphine (heroin) compared to morphine.
Diamorphine (heroin) and morphine have the same functional groups,
except for two. While morphine contains two alcohol groups, diamorphine is synthetically
modified, so that the two alcohol groups are replaced by esters.
Due to the difference in functional groups, diamorphine is much less
polar than morphine. As a result of this, heroin can pass the blood-brain
barrier much quicker in a much larger concentration. The lower polarity of
heroin facilitates the drug’s transportation in the non-polar environment of
the central nervous system (CNS)—remember, likes dissolve likes!
Because heroin requires a secondary reaction in brain, which hydrolyzes
the ester links, another derivative of morphine, 6-monoacetylmorphine, is even
more effective than heroin. 6-monoacetylmorphine has one alcohol and one ester
group.
D9 Drug Design
D.9.1 Discuss the use of a
compound library in drug design.
Compound library is a collection of a very large number of related compounds
produced by combinatorial synthesis techniques. Each chemical in the library
has associated information about its biological activity, such as the effect on
enzymes and ability to bind to certain receptor sites. Researchers can use this
information to find a compound, which fits well the properties of the
researched disease (e.g. polarity, stereoisomerism). The process of creating
compound libraries is lengthy and expensive, so firms must pay royalties to
access the libraries. As opposed to synthesizing and individually evaluating
different compounds for biological properties, this approach allows money and
time to be saved.
D.9.2 Explain the use of
combinatorial and parallel chemistry to synthesize new drugs.
Combinatorial chemistry uses a large number of starting reactants to
create a variety of different compounds. These compounds are then tested for
biological activity, such as the effect on enzymes and the ability to bond to
receptor sites. This information is then stored in combinatorial libraries.
Combinatorial chemistry is very repetitive and lengthy, so it uses a lot of
computer mechanics.
Combinatorial synthesis utilizes solid phase chemistry. Solid phase
chemistry is the following process:
1)
Very small resin beads are made—these provide a surface
for the attachment and reaction of other molecules.
2) Different
molecules are attached to the solid beads. This is called the “mix and split”
method.
3)
The products are cleaved from the beads by filtration
and washing the beads.
Solid phase chemistry can be fully automated and use robotics, which
saves time and money.
Combinatorial chemistry also uses the mix and split method. The advantages
of the combinatorial chemistry are:
1)
Mass testing and screening for biological activity
2)
High efficiency
Parallel synthesis carries out the chemistry to create a single
product. Parallel chemistry can produce much smaller and more focused
libraries.
D.9.3 Describe how computers are
used in drug design.
Three-dimensional molecules can be created in silico, by computer software. An active ingredient can be made
so that the chemical structure of the drug matches the shape of the compound,
which the drug is supposed to affect. For example, an alteration in this
compound may stop the spread of disease—this is the case of the beta-lactam
ring in penicillin. Computer models can also assess the biological and other
effects of compounds without the need to synthesize the chemicals in reality.
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.
The polarity of molecules can be increased to make them more water
soluble. Because ions are the most water soluble, manufacturers try to make
drugs ionic. Many drugs that contain amine group are reacted with hydrochloric
acid and are administered as hydrochloride salt. Many drugs that contain
carboxylic acid group are reacted with a base (e.g. NaOH) and are administered
as their sodium or calcium salt.
Soluble aspirin – makes anion with NaOH; loses H+, so Na+
is attracted to the negative site where H+ was lost
Prozac (fluoxetine hydrochloride) – makes cation with HCl; H+
from HCl bonds to nitrogen in Prozac
Most drugs are distributed around the body through blood—they dissolve
in the blood plasma. Blood plasma is mostly water, a polar solvent. Making a
molecule more polar, i.e. transforming it into its ionic form makes the
chemical more soluble. This facilitates the distribution of the drug around the
human body, i.e. increases the drug’s bioavailability.
D.9.5 Describe the use of chiral
auxiliaries to form the desired enantiomer.
A chiral auxiliary is a compound, much like a catalyst, which is used
to convert non-chiral molecule into just the desired enantiomer. This is
important because sometimes only one enantiomer has the desired pharmacological
effect. The working of chiral auxiliaries is described below:
1)
Chiral auxiliary attaches to a non-chiral reactant.
2) This
creates the stereochemical conditions necessary to force the reaction to follow
a certain path.
3) In
this path, only one enantiomer is formed.
4) Chiral
auxiliary is taken off the product and recycled.
5)
The enantiomer is ready and chiral auxiliary can be used
again.
Chiral auxiliaries are used to synthesize Taxol (paclitaxel), an
anti-cancer drug, which is normally found in the bark of a Pacific yew tree.
Without chiral auxiliaries, enormous quantities of trees would have to be cut
down to meet the demand for Taxol.
D.10.1 Describe the effects of
lysergic acid diethylamide (LSD), mescaline, psilocybin and
tetrahydrocannabinol.
Drug
|
Effects
|
Lysergic acid diethylamide
|
·
Flashbacks
·
Changes in visual and sound perception –
hallucinations; good or bad trips
·
Desire to laugh
·
Hypertension, dilated pupils, change in body
temperature & hearth rate
·
Psychological dependence
|
Mescaline
|
·
Subjective hallucinations
·
Anxiety, static tremors, psychic disturbances
·
Abdominal pain – muscle ache
|
Psilocybin
|
·
Subjective hallucinations milder than with
mescaline
·
Change in mood – pleasant or apprehensive
·
Inappropriate laughter, dizziness
·
Muscle weakness is common
|
Tetrahydrocannabinol
|
·
Appetite stimulation
·
Lethargy, sluggishness
·
Anxiety and irritability
·
Psychological dependence
|
D.10.1 Discuss the structural
similarities and differences between LSD, mescaline and psilocybin.
Should compare all three to the indole ring.
Drug
|
Functional
Groups
|
Lysergic acid diethylamide
|
·
Benzene ring
·
Alkene (2)
·
Secondary amine
·
Tertiary amine
·
Tertiary amide
|
Mescaline
|
·
Benzene ring
·
Primary amine
·
Ether (3)
|
Psilocybin
|
·
Benzene ring
·
Secondary amine
·
Tertiary amine ion
·
Phosphate
|
All three drugs contain benzene ring,
LSD and psolocybin also contain cyclopentene ring (?) with secondary amine, so
they have the indole part. Mescaline misses the secondary amine.
D.10.3 Discuss the arguments for
and against the legalization of cannabis.
Arguments
for:
|
Arguments
against:
|
· Relieves symptoms of Parkinson’s disease
|
·
Stepping stone drug – can lead to the use of
harder drugs
|
·
Source of additional tax revenue
|
·
Increased risk of lung cancer
|
·
No more or less harming than tobacco or
alcohol.
|
·
Risk of driving or manipulation with machinery
under influence, which increases the chance of an injury.
|
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