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Mid-Semester Exam MC3A 2003
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Family Name: __________________
CONFIDENTIAL
Other Names:___________________
Seat Number:___________________
THE UNIVERSITY OF SYDNEY
FACULTY OF PHARMACY
BACHELOR OF PHARMACY DEGREE
THIRD YEAR EXAMINATION
MEDICINAL CHEMISTRY 3A (PHARM 3609) Mid-Semester Exam
May 2003
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Time allowed: 1.5 hours
Non-programmable calculators may be used.
Use the ANSWER SHEET provided to mark clearly in pencil your answer to the
multiple choice questions, 1 to 30
All written answers to questions must be completed on the question paper (pages
12 - 16).
This question paper must be returned to the examiners. No portion of the question
paper may be copied or removed from the examination room by candidates.
The value of each question is shown in the table below and on the paper against
questions .
Marks will NOT be deducted for incorrect answers in the multiple choice
questions.
Space is provided at the end of this question paper for rough work.
Question
1-30
31
32
33
34
35
Marks
60
12
3
11
6
8
•
This examination booklet consists of 17 pages, numbered from 1-17 inclusive. There are
questions numbered from 1- 35 inclusive.
•
Students are asked to check that their booklet is complete, and to indicate that they have
done so by signing, as provided below.
•
Students finding an incomplete booklet should obtain a replacement from the Examination
supervisor immediately.
I have checked this booklet and affirm that it is complete.
SIGNATURE
.....................................................................................................
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Q1. Acetylcholine is a neurotransmitter
A.
B.
C.
D.
E.
at ganglionic synapses of both the parasympathetic and sympathetic
nervous system.
at ganglionic synapses in the parasympathetic nervous system only.
at ganglionic synapses of the sympathetic nervous system only.
at all synapses in the human nervous system.
at synapses in the peripheral nervous system only.
Q2. The acyl (acetyl) group of acetylcholine at muscarinic receptors:
O
+
(CH3 )3 N
A.
B.
C.
D.
E.
CH2 CH2 O
C
CH3
Cl
cannot be altered without loss of agonist activity.
can be changed by only one or two carbons (e.g. propionyl or formyl
groups) with minimal loss of agonist activity.
can be increased by up to five carbons without loss of potency as an agonist.
can be replaced by a benzoyl linkage with retention of agonist activity.
can be replaced by almost any group with retention of agonist activity, since this
site is well away from the onium group.
Q3. The quaternary ammonium group of acetylcholine, with respect to agonist activity
at muscarinic receptors
A.
B.
C.
D.
E.
can be replaced with any medium sized hydrophobic group since it binds to a
hydrophobic cavity on the receptor.
cannot be altered from the trimethylammonium group without almost
complete loss of potency. (?????)
can be increased in size by substitution of two methyl groups with only minimal
loss of potency.
can be increased in size by substitution of three methyl groups with only
minimal loss of potency.
can be increased in size by three methyl substitutions with only minimal loss of
potency.
Q4. The ester linkage in acetylcholine acting as an agonist on muscarinic receptors
A.
B.
C.
D.
E.
cannot be varied without complete loss of activity.
allows acetylcholine to act transiently as a neurotransmitter due to its rapid
hydrolysis by acetylcholinesterase.
limits the usefulness of acetylcholine as a drug because of its transient action.
B and C are correct.
A, B and C are correct.
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Q5. If the ether oxygen (within the ester group) of acetylcholine is changed to a sulphur
(S) atom, the agonist activity at muscarinic receptors is:
A.
B.
C.
D.
E.
unaffected.
lost completely.
retained, but with lower potency, because thiol esters are hydrolysed only slowly
by acetylcholinesterase.
retained, but with lower potency, because it produces a lower maximal response
(low intrinsic activity).
retained, but with considerably lower potency, because S has altered
electronic and hydrophobic properties compared to oxygen.
Q6. The specificity of acetylcholine for muscarinic receptors relative to nicotinic
receptors can be INCREASED by:
A.
B.
C.
D.
E.
altering the acetyl group to a carbamate (O-CO-NH2) group
altering the acetyl group to a carbamate and addition of a methyl substituent on
the carbon in the position - to the onium group.
addition of a methyl substituent on the carbon in the position - to the
onium group.
all of the above.
B and C are correct.
Q7. The specificity of acetylcholine for muscarinic receptor subtypes:
A.
B.
C.
D.
E.
cannot be achieved because acetylcholine analogues must retain conformational
flexibility in order to interact with muscarinic receptors.
can be achieved by alterations in the acyl group.
can be achieved by alterations of both the acyl and onium groups.
can be achieved by making the molecule rigid through restriction of
freedom of rotation of certain bonds.
can be achieved only with naturally occurring compounds (e.g. pilocarpine,
muscarine).
Q8. An accepted pharmacophore model for the acetylcholine muscarinic receptor has
the following features:
A.
B.
C.
D.
E.
An onium anionic binding site.
A hydrogen bonding (or dipole-dipole) site 3A from the onium site.
A methyl cavity.
All of the above.
A and B are correct.
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Q9. Introduction of a -methyl substituent in the side chain of acetylcholine
A.
B.
C.
D.
E.
has no effect on biological activity. (since all it does is decrease likelihood of
hydrolysis).
will enhance muscarinic receptor potency irrespective of the stereospecificity of
the substitution.
will enhance muscarinic receptor selectivity only when the methyl substitution is
stereospecific ( (+)-configuration ).
only when the methyl substitution is stereospecific ( (-)-configuration ).
is irrelevant, since there is no asymmetric centre created.
Q10. A therapeutically useful muscarinic receptor antagonist may be obtained as
follows:
A.
B.
C.
D.
E.
from natural plant sources.
by adding one aromatic ring to the acetyl function of the acetylcholine backbone.
by adding two aromatic rings and a hydroxyl group to the acetyl group of
the acetylcholine backbone. (also requires larger groups on the onium
head??)
A, B and C above.
A and C above.
Q11. For anti-muscarinic an optimal distance between the onium nitrogen and the
hydrophobic substituents in the acyl portion of acetylcholine is achieved
A.
with a variety of linkage structures.
B.
only when the ester linkage of acetylcholine is retained.
C.
only when there is a non-ester linkage between functional groups.
D.
only when the linkage is formed by a cyclic ring.
E.
only when there is a –OH substituent in the linkage group.
Q12. Subtype selective muscarinic receptor antagonists are
A.
B.
C.
D.
E.
naturally occurring (e.g. plants such as deadly nightshade).
synthetic derivatives with a structure often totally unlike that of atropine or
acetylcholine.
structures that appear unrelated to acetylcholine but in fact have a similar
electronic arrangement of groups (e.g. analogs of oxotremorine).
structures that are less conformationally flexible than acetylcholine or
atropine, and have conformations favouring a particular receptor (e.g. M1
receptors). ??????????????
not available yet.
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Q13. The following structure (DMPP or dimethylphenylpiperazine chloride) is a
nicotinic receptor agonist for the following reasons
+
N
CH3
N
Cl
CH3
A.
B.
C.
D.
E.
DMPP
It provides a two point attachment (the positive nitrogen and the
electronegative N-phenyl group).
It provides a three point attachment, as in all known drug receptor interactions.
It provides an onium group analogous to the trimethylammonium group in
acetylcholine.
It is a bis-onium compound related to the ganglion blocker hexamethonium.
A and C above.
Q14. Nicotine and dimethylphenylpiperazinium share the following common features
A.
B.
C.
D.
E.
They both block the ganglionic nicotinic receptor by bridging two anionic sites.
They both block the ganglionic nicotinic receptor by depolarising the
postganglionic nerve, eventually leaving the cell refractory to the action of
acetylcholine.
They both act to competitively block access of acetylcholine to the receptor.
They both are currently applied therapeutically to lower blood pressure.
None of the above.
Q15.
O
+
(CH3 )3 N
(CH2 )10
+
N(CH3 )3
+
(CH3 )3 N
CH 2 CH2 O
C
CH2
2
Decamethonium and succinylcholine are neuromuscular blockers
A.
B.
C.
D.
E.
with a similar hydrophobicity.
with a similar distance separating their trimethylammonium groups.
with the same pharmacokinetics of neuromuscular blockade.
which differ in the duration of neuromuscular blockade due to differences in
their hydrophobicities.
B and C are correct.
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Q16. Comparing decamethonium and d-tubocurarine
A.
B.
C.
D.
E.
they both produce neuromuscular (NM) blockade by a similar mechanism of
action.
decamethonium’s NM blockade can be overcome by increasing the
concentration of acetylcholine at the NM junction.
d-tubocuranine’s NM blockade can be overcome by increasing the
concentration of acetylcholine at the NM junction.
decamethonium was developed from d-tubocuranine by maintaining the same
distance between the ammonium groups (14A).
C and D are correct.
Q17.
d-tubocurarine
CH3
HO
+
NH
CH2
OCH3
O
CH2
+
N
H3 CO
O
H3 C
CH3
HO
d-tubocurarine is the basis of newer NM junction blockers by upholding the following
principles:
A.
B.
C.
D.
E.
the distance between the two ammonium groups is around 14A.
the chemical scaffold separating the two ammonium groups must be based on
that of the acetylcholine molecule.
the chemical scaffold between the ammonium groups exhibits wide structural
variation (e.g. steroid structures, tetrahydroisoquinolines).
A and B are correct.
A and C are correct.
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Q18.
O
O
C
CH 3
N
CH 3
+
(CH 3 )3N
X
Neostigmine is an acetylcholinesterase inhibitor with the following properties.
A.
B.
C.
D.
E.
reversible, with a similar mechanism of action to Tacrine.
reversible, but it forms a covalent interaction with the enzyme which is
extremely short lived (microseconds).
reversible, but it forms a covalent interaction with the enzyme which has a
medium lifetime (minutes).
reversible, but it forms a covalent bond with the enzyme which has a long
lifetime (hours).
irreversible, because it forms a covalent bond with the enzyme esteratic site.
Q19. Neostigmine can be used therapeutically as follows
A.
B.
C.
D.
E.
For glaucoma due to its inhibition of acetylcholine breakdown and very long
onset and duration of action (hours to days).
for glaucoma, due to its inhibition of acetylcholine breakdown, and medium
onset and duration of action (minutes to hours).
as an insecticide due to its anticholinesterase activity and destruction of insect
CNS following uptake across the cuticle.
A and C.
B and C.
Q20. Organophosphates, such as malathion, are:
A.
B.
C.
D.
E.
essentially irreversible inhibitors of acetylcholinesterase, useful as
insecticides for many days.
essentially irreversible inhibitors of acetylcholinesterase, with limited usefulness
as insecticides, because the inhibition is readily reversed on contact with water.
irreversible inhibitors of acetylcholinesterase, because they interact with a serine
hydroxyl group in the active site and the reaction is reversed within tens of
minutes.
irreversible inhibitors of acetylcholinesterase because they react with the
imidazole nitrogen in the esteratic site.
not used widely as insecticides because there is no antidote to agricultural
poisoning.
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Q21.
Pralidoxime is effective as an antidote for organophosophate-inhibited
acetylcholinesterase due to:
+
N
CH
N
OH
I
CH3
A.
B.
C.
D.
E.
Pralidoxime
it being a quaternary ammonium compound which is orientated towards the
active site by interaction with the ammonium binding site of the enzyme.
the oxime group which is a strong nucleophile and attacks the electrophilic
phosphorylated-enzyme bond.
the presence of both the ammonium group and the oxime group in adjacent
positions on the aromatic ring.
the presence of both the ammonium group and the strong oxime nucleophilic
group, irrespective of the distance between the two groups.
the ability of the pralidoxime to form a complex with the organophosphate,
thereby preventing it from being absorbed and hence reacting with the
acetylchoinesterase.
Q22. A patient who has been poisoned by an organophosphate should be treated as
follows:
A.
B.
C.
D.
E.
A muscarinic agonist plus pralidoxime.
A muscarinic antagonist plus pralidoxime given at any time after ingestion.
A muscarinic antagonist followed by pralidoxime within one minute.
A muscarinic antagonist followed by pralidoxime given within a few hours of
ingestion.
pralidoxime alone, since muscarinic antagonists (such as atropine) are toxic and
the pralidoxime has sufficient antimuscarinic potency of its own.
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Q23. The following is the structure of noradrenaline.
HO
HO
CH
CH2 NHCH3
OH
The compound is
A.
B.
C.
D.
E.
a phenylethylamine.
a catecholamine.
a neurotransmitter at all sympathetic nerves.
a neurotransmitter at all central and peripheral nerves.
A and B above.
Q24. Noradrenaline is more potent than isoprenaline at -adrenergic receptors because
A.
B.
C.
D.
E.
it is a catecholamine.
it has a small substituent on the nitrogen in the ethylamine side chain.
it has an hydroxy group in the ethylamine chain.
All of the above.
B and C are correct.
Q25. The duration of action of noradrenaline has been increased as follows
A.
B.
C.
D.
E.
by substituting the 3,4-dihydroxy aromatic substituent with a 3,5-dihydroxy
substituent.
by removing the catechol groups catechol, hence preventing metabolism by
catechol O-methyl transferase.
by shortening the length of the ethylamine side chain.
by removing the hydroxyl substitution in the ethylamine side chain, and hence
preventing oxidation by cytochrome P450.
All of the above.
Q26. Isoprenaline has an isopropyl group substituent on the ethylamine nitrogen in
place of the methyl substituent in noradrenaline. This provides it with the following
features.
A.
B.
C.
D.
E.
increased potency for both  1 and  2 adrenergic receptors.
increased potency for 2 receptors in the bronchial smooth muscle.
Both  and -adrenergic potency, with marginal -receptor selectivity.
greater resistance to both catecholamine-transferase and monoamine oxidase
metabolism.
A and D are correct.
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Q27. Selective 2 adrenergic receptor antagonists such as salbutamol, useful in asthma
by pulmonary inhalation administration, have the following properties:
OH
HC
CH2
NH
C(CH3 )3
CH2 OH
A.
B.
C.
D.
E.
OH
enhanced duration of action due to not being a catecholamine.
a hydroxy substituent in the side chain, which allows a central component of
action.
the presence of isopropyl group substitution on the nitrogen, which makes the
compound a partial -receptor antagonist.
All of the above.
A and B above. (I THINK b also because Beta must have at least one
substituent. But I don’t’ know… )
Q28. Propranolol, shown below, demonstrates the following features in the design of
adrenergic blockers.
CH3
O
NH
CH3
OH
A.
B.
C.
D.
E.
An isopropyl group, which enhances adrenergic receptor interaction.
An hydroxy group in the side chain, which provides receptor interaction.
A bulky aromatic substituent appropriately separated from the ethylamine linker.
A sufficiently subtle substitution on the catechol group of isoproterenol, which
provides some partial agonist activity.
All of the above.
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Q29. Amphetamines are sometimes abused because
CH 3
CH2 CH
A.
B.
C.
D.
E.
NH 2
they are direct acting catecholamines which interact with CNS adrenergic
receptors, producing an “adrenaline rush”.
they are indirect acting agents because they lack the catechol group.
they cross the blood-brain barrier being more hydrophobic than the direct acting
catecholamines because of the lack of a side chain hydroxy group and/or the
presence of an alkyl substituent.
they release noradrenaline and adrenaline after being taken up into the nerve
endings.
B, C and D are correct.
Q30. The difference in pharmacological activity between clonidine and naphazoline is
as follows:
Cl
N
H
N
CH2
N
H
N
N
H
Cl
Naphazoline
Clonidine
A.
B.
C.
D.
E.
Naphazoline has a -CH2- group in place of the -N=, so that it acts on different
receptors to clonidine.
Clonidine is more hydrophobic in character, hence crosses the blood brain
barrier and interacts with  receptors, blocking the release of catecholamines in
the periphery.
Clonidine is more hydrophobic in character, hence crosses the blood brain
barrier and interacts with 2 receptors, blocking the release of catecholamines in
the periphery.
A and B are correct.
A and C are correct.
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Q31. Joe Blow aged 18 was diagnosed with schizophrenia. He was initially prescribed
chlorpromazine but later given clozapine. (Total 12 marks)
(i)
(ii)
(iii)
(iv)
What are the main structural features important for antipsychotic activity
associated with chlorpromazine? (3 marks)
What conformation does the propyl side chain adopt when binding; do all
conformations have activity? Explain your answer. (3 marks)
What receptor(s) does chlorpromazine bind to and how does this equate to
any side effects? (3 marks)
Compare and contrast the therapeutic effects of chlorpromazine with
clozapine. (3 marks)
CH3
N
N
S
Cl
N
(CH2 )3
Cl
N(CH3)2
Chlorpromazine
N
N
H
Clozapine
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Q32. Sumatriptan was developed as an anti-migraine drug. What is the mode of action?
(3 marks)
N(CH3)2
H3 C
NH
O
S
O
Sumatriptan
N
H
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Q33. As the Chief Medicinal Chemist of Pain Therapeutics, Inc., you are in charge of
drug design and development. You have been asked by the Managing Director (MD) to
design and develop a drug for pain management superior to morphine. Your tasks
involve:
(i)
Evaluating the structure-activity relationship of the C-ring of morphine. (5
marks)
(ii)
Determine how you would convert morphine, a µ opioid agonist, into a µ
opioid antagonist. (4 marks)
(iii) Give an example of a µ opioid antagonist and what is its clinical application.
(2 marks);
HO
O
NCH3
H
HO
Morphine
i)
- converting the OH at the 6 position to a keto will increase activity
- removing the 7-8 double bond will allow the molecule to adopt a chair conformation
(rather than the boat) and activity will increase
- adding a OH group at the 14 position will increase activity
- Do no place the OH at the 8 position as this will decrease activity
ii) Firstly, we can change the N group into an allyl group or a cyclopentylmethyl group.
This will give the molecule some antagonistic activities but will also retain some agonist
activity (nalorphine). Inserting OH at the 14 position will sterically hinder the molecule
such as the n group will be away from the OH. This configuration preferentially acts as a
mu antagonist.
iii) naloxone which is used to treat heroin overdose and recover breathing depression.
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Q34. Discuss the metabolism of codeine and determine why codeine is less potent as an
analgesic than morphine? (6 marks)
Codeine has a CH3O at the three position instead of the OH group of morphine. It is less
potent than morphine due to this group. When the 3 position is protected, it does not
interact with the opiod receptors, making codeine more effective as an anti-tussive.
However, codeine does have some analgesic effect because 10% of codeine is converted
into normorhpine where O methylation occurs first, followed by N demethylation. 90%
of the molecule then goes to N demethylation without first undergoing O demethylation.
It is also possible for conjugation to occur at the 3 position and glucoronidation to occur
at the 6 position. (insert structures).
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Q35. Most local anaesthetics are tertiary amines (pKa 7.0-9.0) that block nerve
conductance by binding to selective site(s) on the voltage-gated Na+ channel. Briefly
outline the local anaesthetic pharmacophore and explain why the cation-to-base ratio is
critical to nerve conduction block. (8 marks)
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Space provided for rough working
If JD took morphine tablets would she be suffering from respiratory depression?
Explain your
answer in terms of the metabolic pathway(s) of heroin and morphine. Show
chemical structures
where appropriate (6 marks).
Yes she would be.
Because of the two acetyl groups, heroin is quickly hydrolysed in the body to produce
morphine. The ease of hydrolysis means that the conversion is 100%. It is this morphine
that is responsible for the breathing depression and so taking pure morphine will result
in the similar outcomes.
(ii) Draw the structure of naloxone. What chemical features are needed to
convert morphine into the µ-opioid antagonist naloxone? Explain why (6
marks)?
The 7-8 double bond is removed to increase activity
The OH at the 6 position is replaced by the keto to increase acitivty
The OH at the 3 position is free to bind with opioid receptors
The N group is converted into an allyl group or a cyclopentylmethyl group in order to
give it antagonistic activity
Oh is added in the 14th position to sterically hinder the N group such that it is
preferentially an antagonist.
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The methyl group at the 2 position gives good torsion angles to improve
selectivity.
This methyl group also protects the N in the ring and prevents P450 degradation.
There is no substitution at the 2 or 6 position on the biaryl group which reduces
activity due to steric interaction
We have improved hypolocomotor activity
Substituent at 4 position increases activity and oral availability.
Also have good activity if F on 5 position