Download Tutorial - 4: Respiratory Drug Development

Medicinal Chemistry-III, Tutorial - 3
M edicinal Chemistry – III
Tutorial – 4 (Home Work)
Respiratory Drug Development
1. Write the name and clinical use of the following drugs. Briefly explain why the
compound (2) has better activity than compound (1).
OH
HO
H
N
CH
C CH3
3
CH3
H3C
CH3
N
O
OH
O
H CH3
N
C CH3
CH3
CH3
N
CH3
O
OH
O
(1)
(2)
Answer:
 Structure (1) is terbutaline, a selective β2 adrenoceptor agonist used as a bronchodilator
for the treatment of asthma.
 Structure (2) is bambuterol, an orally active long acting β2adrenoceptor agonist used
in the treatment of asthma.
 Terbutaline has short duration of action due to the enzymatic degradation of meta
hydroxyl group by catechol O-methyltransferase (COMT).
 Bambuterol is a prodrug of terbutaline where the 2 OH groups attached to phenyl ring
were masked by converting them into biscarbamate.
 Bambuterol is stable to COMT increasing the duration of action.
 The advantage of bambuterol over terbutaline is that it's given once a day and increases
the likelihood of patient compliance.
2. Account for the greater biological activity of (R)-orciprenaline when compared to its
(S)-enantiomer. What effect on potency would you expect from the removal of the
alcoholic (OH) group from R-orciprenaline?
Answer:
 The secondary hydroxyl group (OH) of only R-enantiomer can form hydrogen bonding
interaction with the crucial amino acid residue Asn293 at the binding site of the receptor
whereas the S-enantiomer cannot form this interaction. Hence R-enantiomer of
orciprenaline is biologically more active than S-enantiomer.
 Removal of the alcoholic (OH) group from the active enantiomer of orciprinaline (Renantiomer) would reduce the potency as there would be no hydrogen bonding
interaction with the crucial amino acid residue Asn293 at the binding site of the
β2 -adrenoceptor.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
3. Terbutaline is superior to orciprenaline in the management of asthma for a patient
suffering from cardiac hypertension. Illustrate how the chemistry of these drugs
explains this observation from the point of view of side effects and improvement of
activity.
Answer:
 The isopropyl group attached to the secondary N-atom of orciprenaline fit into the
hydrophobic pocket of the binding site of cardiac β1 receptor in the heart along with the
β2 receptor in the lungs which may enhance cardiac blood pressure due to β1 agonism
and cause many deaths due to aerosol overdoses.
 Terbutaline has a bulky tertiary butyl group attached to the secondary N-atom which
prevents it to fit into the smaller hydrophobic pocket of the binding site of cardiac β1
receptor in the heart due to steric hindrance giving enhanced selectivity for the β 2
receptor in the lungs. Thus terbutaline has no cardiac side effect.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
4. Write the structures of (R) and (S)-enantiomers of terbutaline. Explain which enantiomer
has greater biological activity by highlighting the interaction of important functional
group(s) of the active enantiomer with the β2 receptor. Your answer should include the
hypothetical binding mode of the active enantiomer at the binding site of the receptor.
Answer:
The structures of (R) and (S)-enatiomers of terbutaline are
The R-enantiomer of terbutaline has more biological activity than S-enantiomer.
R-enantiomer of terbutaline forms the following interactions with the β2 receptor:
 The hydroxyl group (OH) attached to meta-position of the aromatic ring forms essential
hydrogen bonding interaction with the Ser207 at the binding site of the receptor.
 Alkylammonium ion forms an ionic bond to the binding site (Asp113) of the receptor.
 Bulkier t-butyl group is responsible for selectivity towards β2 adrenoceptor by
selectively occupying the hydrophobic pocket of the binding site of β2 adrenoceptor.
 Aromatic ring forms van der Waals interactions (π-π stacking) with the phenyl ring of
Phe290 at the binding site of the receptor.
 The secondary hydroxyl group (OH) of only R-enantiomer can form hydrogen bonding
interaction with the crucial amino acid residue Asn293 at the binding site of the receptor
whereas the S-enantiomer cannot form this interaction. Hence R-enantiomer of
terbutaline is biologically more active than S-enantiomer.
Fig. Binding interactions of R-enantiomer of terbutaline with β2 adrenoceptor.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
5. What effect on potency would you expect from the removal of the alcoholic (OH)
group from the active enantiomer of terbutaline?
Answer:
Removal of the alcoholic (OH) group from the active enantiomer of terbutaline (Renantiomer) would reduce the potency as there would be no hydrogen bonding
interaction with the crucial amino acid residue Asn293 at the binding site of the
β2 -adrenoceptor.
6. Terbutaline undergoes metabolism to give the inactive metabolite due to the
enzymatic degradation by catechol O-methyltransferase (COMT). Write the
structure of the metabolite and briefly explain why this metabolite is inactive?
Answer:
The metabolite structure of terbutaline is given below:
This metabolite of terbutaline is inactive as it cannot form essential H-bonding interaction
with the crucial amino acid residues Ser207 at the binding site of the β2-receptor.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
7. Salbutamol is superior to isoprenaline in the management of asthma. Illustrate how
the chemistry of these drugs explains this observation from the point of view of side
effects and improvement of activity. Your answer should include the chemical
structures of the metabolites of the drugs.
OH
HO
H
N
HO
OH
CH3
CH
CH3
HO
Isoprenaline
HO
H
N
CH
C CH3
3
CH3
Salbutamol
Answer:
The isopropyl group attached to the secondary N-atom of isoprenaline fit into
the hydrophobic pocket of the binding site of cardiac β1 receptor in the heart along with
the β2 receptor in the lungs which caused many deaths due to aerosol overdoses on the
heart (due to β1 agonism). It has short duration of action due to the enzymatic
degradation by catechol O-methyltransferase (COMT) to form the inactive 3-Omethyl isoprenaline. It also has poor oral activity due to the formation of
isoprenaline-4-O-sulfate by sulfokinases in the gut wall.
OH
H3CO
OH
HO
O-methyltransferase
(COMT)
H
N
HO
CH3
CH
CH3
HO
CH3
CH
CH3
3-O-methyl isoprenaline
OH
Isoprenaline
H
N
sulfokinases
HO
HO.O2SO
H
N
CH3
CH
CH3
Isoprenaline-4-O-sulphate
Salbutamol has a bulky tertiary butyl group attached to the secondary N-atom which
prevents it to fit into the smaller hydrophobic pocket of the binding site of the cardiac
β1 receptor in the heart due to steric hindrance giving enhanced selectivity for the β2
receptor in the lungs. Thus salbutamol has no cardiac side effect. Moreover, the
hydroxymethyl group attached to the phenyl ring made it stable to COMT
increasing the duration of action.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
8. Write the structures of (R) and (S)-enantiomers of salbutamol. Explain which enantiomer
has greater biological activity by highlighting the interaction of important functional
group(s) of the active enantiomer with the β2 receptor. Your answer should include the
hypothetical binding mode of the active enantiomer at the binding site of the receptor.
Answer:
The structures of (R) and (S)-enatiomers of salbutamol are
HO
HO
H H
N
HO
CH
C CH3
3
CH3
(S)-salbutamol
H
HO
HO
OH H
N
CH
C CH3
3
CH3
(R)-salbutamol
The R-enantiomer of salbutamol has more biological activity than S-enantiomer.
R-enantiomer of salbutamol forms the following interactions with the β2 receptor:
 The hydroxymethylene and hydroxyl group (OH) attached to meta and para position
of the aromatic ring form essential hydrogen bonding interaction with the amino acid
residues Ser207 and Ser204 at the binding site of the receptor.
 Alkylammonium ion forms an ionic bond to the binding site (Asp113) of the receptor.
 Bulkier t-butyl group is responsible for selectivity towards β2 adrenoceptor.
 Aromatic ring forms van der Waals interactions (π-π stacking) with the phenyl ring of
Phe290 at the binding site of the receptor.
 The secondary hydroxyl group (OH) of only R-enantiomer can form hydrogen bonding
interaction with the crucial amino acid residue Asn293 at the binding site of the
receptor whereas the S-enantiomer cannot form this interaction. Hence R-enantiomer
of salbutamol is biologically more active than S-enantiomer.
Draw structure of drug with binding interaction
Fig. 3. Binding interactions of R-enantiomer of salbutamol with β2 adrenoceptor.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
9. Describe the development process which led to the discovery of isoprenaline starting from
adrenaline. Use chemical structures to clearly illustrate the key structural changes made in
the process, describe why those changes were made and specify the outcomes that these
changes had on both the physicochemical and biological properties.
Answer:
Write yourself.
10. Which of the following drug is superior in the management of asthma for a patient suffering from
cardiac hypertension? Give reasons.
Answer:
Terbutaline is superior in the management of asthma for a patient suffering from
cardiac hypertension because of the following reasons:

The isopropyl group attached to the secondary N-atom of orciprenaline fit into the
smaller hydrophobic pocket of the binding site of cardiac β1 receptor in the heart
along with the larger β2 receptor in the lungs which caused many deaths due to
aerosol overdoses on the heart (due to β1 agonism).

Terbutaline has a bulky tertiary butyl group attached to the secondary N-atom which
prevents it to fit into the smaller hydrophobic pocket of the binding site of the
cardiac β1 receptor in the heart due to steric hindrance giving enhanced selectivity
for the β2 receptor in the lungs. Thus terbutaline has no cardiac side effect.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
11.
Which of the following statements is FALSE regarding salbutamol?
OH
HO
H
N
CH3
C CH
3
CH3
HO
Salbutamol (logP 0.11)
A.
B.
C.
D.
12.
Which of the following anti-asthmatic drug cannot be given to a patient suffering from
hypertension?
A.
B.
C.
D.
13.
Eformoterol
Isoprinaline
Salbutamol
Terbutaline
Which of the following drug is a selective β2-adrenoreceptor agonist?
A.
B.
C.
D.
14.
It is stable to COMT metabolism.
It is non-selective β-adrenoreceptor agonist.
R-enantiomer is more active than S-enantiomer.
It can be a beneficial anti-asthmatic agent for a patient suffering from cardiac
hypertension.
Adrenaline
Isoprenaline
Orciprenaline
Salmeterol
Which of the following β2-adrenoreceptor agonist is stable to both COMT and sulfokinase but
can cross blood brain barrier and shows CNS side effects?
A.
B.
C.
D.
Adrenaline
Ephedrine
Orciprenaline
Salbutamol
Dr Pran Kishore Deb