medicinal chemistry

1. © Oxford University Press, 2013
ANTIDEPRESSANT
AGENTS
Patrick: An Introduction
to Medicinal Chemistry 6e
Case study 7

2. © Oxford University Press, 2013
1. Depression
• Affects 10% of the population
• 340 million sufferers worldwide
• Predicted to be second leading ailment by 2020
• Symptoms - misery, apathy, pessimism, low self esteem, guilt,
inability to concentrate or work, loss of libido, poor sleep,
loss of motivation, loss of appetite
• Causes - genetic predisposition or a stressful life-changing
event

3. © Oxford University Press, 2013
• Deficit of monoamine neurotransmitters in the brain
• Dopamine, serotonin and noradrenaline
Dopamine Serotonin
(5-Hydroxytryptamine)
Noradrenaline
N
H
HO
NH2
HO
HO
NH2
OH
HO
HO
NH2
2. Monoamine hypothesis

4. © Oxford University Press, 2013
Evidence
• Clinically important antidepressants increase monoamine levels
• Reserpine lowers monoamine levels and causes depression
Reserpine
N
H
N
H3CO
H H
H
H3CO2C O
OCH3
O
OCH3
OCH3
OCH3
2. Monoamine hypothesis

5. © Oxford University Press, 2013
Anomalies
Agents that increase monoamine levels, but have no
antidepressant activity
Amphetamine
NH2
CH3
N
CO2Me
O
CH3
O
H
H
Cocaine
2. Monoamine hypothesis

6. © Oxford University Press, 2013
3. Monoamine oxidase inhibitors (MOAIs)
Notes
• Inhibit metabolism of monoamines
• Increase monoamine levels
• First-generation antidepressants
• Low target selectivity
• Side effects
• Superseded by tricyclic antidepressants
Phenelzine
NHNH2
N
N
H
H
N
O
Me
Me
NH2
Iproniazid Tranylcypromine

7. © Oxford University Press, 2013
‘Cheese reaction’
• MOAIs interact with other drugs and food
• Ripe cheese contains tyramine
• Tyramine is metabolised by MOAs in the gut wall and liver
• MOAIs increase levels of tyramine, leading to acute hypertension and
severe headaches
• Moclobemide is a reversible inhibitor that is MAO-A selective
• High levels of tyramine displace moclobemide from MAO-A in the gut
• Allows metabolism of tyramine in the gut
Moclobemide
3. Monoamine oxidase inhibitors (MOAIs)

8. © Oxford University Press, 2013
4. Tricyclic antidepressants (TCAs)
Notes
• First-generation antidepressants
• Major treatment during the 1960s-1980s
• Low target selectivity
• Several side effects are associated with their use
Desipramine
N
N
H
Me
N
N
Me
Me
N
Me
Me
Imipramine Amitriptyline

9. © Oxford University Press, 2013
Mechanism of action
Inhibit noradrenaline reuptake into presynaptic neurons
Inhibit transport proteins for noradrenaline and serotonin
Noradrenaline
Adrenergic receptor
Transport protein
Presynaptic receptor
TCAs
4. Tricyclic antidepressants (TCAs)

10. © Oxford University Press, 2013
Notes
• Non-planar, V-shaped molecules
• Overlay with noradrenaline matches aromatic ring and amine
• Planar tricyclics are inactive - one ring occupies the region for the amine
Noradrenaline
Desipramine
Overlay
O
O O
N
N
N N
N
N
O
O O
4. Tricyclic antidepressants (TCAs)

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Side effects
• Interact with sodium and calcium ion channels in the heart
• Interact with H1 histamine receptors
• Interact with M1 receptors
• Interact with a1 adrenoceptors
• Results in cardiotoxicity
• Tertiary amines have the greatest side effects on the
cholinergic system
4. Tricyclic antidepressants (TCAs)

12. © Oxford University Press, 2013
5. Selective serotonin reuptake inhibitors (SSRIs)
Notes
• Second-generation antidepressants
• Introduced in the 1980s
• Selctively block reuptake of serotonin to presynaptic neurons
• Block the transport protein for serotonin
• More selective with less side effects
• Slow onset of action (2-6 weeks)
• Negative effect on the libido

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5. Selective serotonin reuptake inhibitors (SSRIs)
Examples
Notes
• S-Enantiomer of citalopram is more active than the R
• Escitalopram is an example of chiral switching

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5. Selective serotonin reuptake inhibitors (SSRIs)
Examples
Sertraline Paroxetine Fluvoxamine

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Notes
• Third-generation antidepressants
• Better selectivity than TCAs
• Reboxetine marketed in 2003
• No action on cholinergic or adrenergic receptors
• Rapidly desensitises presynaptic a2-adrenoceptors
• Decreases feedback inhibition by noradrenaline
• Enhances activity
• Speeds up onset of action
6. Selective noradrenaline reuptake inhibitors
Reboxetine

16. © Oxford University Press, 2013
7. Serotonin and noradrenaline reuptake inhibitors
(SNRIs)
Notes
• Third-generation antidepressants
• Dual-action agents
• Selective inhibitors of serotonin and noradrenaline reuptake
• More selective than classical TCAs
Venlafaxine
O
S
MeHN
Duloxetine Bupropion
Cl
O
Me
N
H

17. © Oxford University Press, 2013
8. Examples of current targets for research
• Transport proteins for dopamine, serotonin, and
noradrenaline
• Adrenergic receptors (a2-adrenoceptor)
• Serotonin receptors (5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7)

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9. Targets for dual-action agents
• Inhibition of both noradrenaline and serotonin transport
proteins
• Antagonism of a2-adrenoceptors and agonism of 5-HT-
receptors
• Inhibition of serotonin transport protein and antagonism of
5-HT1A receptor (autoreceptor on serotonin presynaptic
neurons)
• Inhibition of serotonin transport protein and antagonism of
5-HT2A receptor (responsible for sexual dysfunction)

19. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Serotonin receptors
• Seven known types of serotonin receptor (5-HT1 to 5-HT7)
• Subtypes of each receptor exist
• 5-HT7 -receptor is thought to have a role in depression
• 5-HT7 -antagonists have antidepressant properties in animal
studies
• 5-HT7 -receptors play a possible role in feedback control
• Selective antagonists may have potential as antidepressants

20. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Lead compound
• Discovered by SmithKline Beecham
• High-throughput screening of a compound bank
• Identified a sulphonamide with slight selectivity
Asymmetric
centre
Piperidine
Sulphonamide
Naphthalene
Asymmetric
centre
Structure I
pKi 7.2
S
N
O
O
Me
Me
N
Me

21. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Lead compound
• Structure I was tested as a mixture of 4 stereoisomers
• Stereoisomers were separated and tested
• R,R-Diastereomer has best activity
Structure I
pKi 7.2
S
N
O
O
Me
Me
N
Me

22. © Oxford University Press, 2013
Structure II
pKi 6.9
10. Antagonists for the 5-HT7 receptor
Lead compound
• Structure I was tested as a mixture of 4 stereoisomers
• Stereoisomers were separated and tested
• R,R-Diastereomer has best activity
S
N
O
O
Me
Me
N
Me
R
R

23. © Oxford University Press, 2013
Notes
• One of the asymmetric centres is not essential for activity
• Simplification strategy - remove non essential centre
Essential
Not essential
10. Antagonists for the 5-HT7 receptor
S
O N
O
Me
Me
N
Structure III - no activity
S
O N
O
Me
Me
N
Me
Me
Structure IV - no activity
Structure II
pKi 6.9
S
N
O
O
Me
Me
N
Me
R
R

24. © Oxford University Press, 2013
Notes
10. Antagonists for the 5-HT7 receptor
• Methyl substituent is important for activity
• Binds to a hydrophobic pocket
• Retain methyl group but shift to different position
Group shift
S
O N
O
Me
Me
N
Me
Structure V
pKi 7.5
Essential
Not essential
Structure II
pKi 6.9
S
N
O
O
Me
Me
N
Me
R
R

25. © Oxford University Press, 2013
S
O N
O
Me
Me
N
Me
Structure V
pKi 7.5
10. Antagonists for the 5-HT7 receptor
Conformation analysis of structure V
Restricted rotation

26. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Stable conformation of structure V
Sawhorse diagram
S
N
Me
Me
O
O
N
Me
H
Notes
• Gauche conformation represents an energy minimum
• Possible active conformation
60o
60o
Newman diagram

27. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Rigidification of structure V
• Introduce a ring to lock the molecule into the gauche conformation
• Docking studies carried out on receptor homology model of binding site
• R-Enantiomer of a 6-membered ring is predicted to bind well
Structure V Rigidification
6-Membered ring
Rigidification
5-Membered ring

28. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Rigidification of structure V
S
N
Me
Me
O
O
N
Me
H
R
Structure V
pKi 7.5
Rigidification
S
N
O
O
N
Me
R
Structure VI
pKi 7.8
Ring contraction
S
N
O
O
N
Me
R
Structure VII
pKi 8.0

29. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Further design
Simplication
Me
S
N
O
O
N
Me
Structure VIII
pKi 8.5
Notes
• Phenol group is good for activity (H-bonding interaction)
• Methoxy substituent is less active
• Confirmed by docking studies on model binding site
Phenol
S
N
O
O
N
Me
R
Structure VII
pKi 8.0
Variation of
substituents
HO
S
N
O
O
N
Me
SB 269970
pKi 8.9

30. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Notes
• 250-fold selectivity for the 5-HT7 receptor over 13 other receptors tested
• 50-fold selectivity for the 5-HT7 receptor over the 5-HT5A receptor
• 100-fold selectivity over 50 other receptors, enzymes or ion channels
• Inverse agonist
• Phenol is prone to Phase II conjugation reactions
• Results in rapid excretion
SB 269970
pKi 8.9
HO
S
N
O
O
N
Me
Further design

31. © Oxford University Press, 2013
Methyl group
10. Antagonists for the 5-HT7 receptor
Notes
• Phenol is replaced with an indole as a bioisostere
• Same binding interactions (HN vs HO)
• Rapidly cleared from blood and zero bioavailability in rats
• Methyl substituent is likely to be prone to metabolism
Structure IX
pKi 8.6
S
N
O
O
N
Me
HN
Bioisosteres
Indole
HO
S
N
O
O
N
Me
Further design
SB 269970
pKi 8.9

32. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
Notes
• Methyl group is replaced with an extended substituent
• Molecular modeling indicated a vacant hydrophobic pocket
• Structure X has lost selectivity vs a1B-adrenoceptor
Extension
S
N
O
O
N
HN
O
F
Structure X
pKi 9.08 Fluorobenzoyl
grooup
HO
S
N
O
O
N
Me
Further design
SB 269970
pKi 8.9
Methyl group
Structure IX
pKi 8.6
S
N
O
O
N
Me
HN
Bioisosteres
Indole

33. © Oxford University Press, 2013
10. Antagonists for the 5-HT7 receptor
• Better selectivity and better balance of properties
• Longer lifetime in the blood supply
• Oral bioavailability is 16%
• Taken forward as the basis for further studies
S
N
O
O
N
HN
O
F
Structure X
pKi 9.08 Fluorobenzoyl
grooup
S
N
O
O
N
O
HN
Cl
Variation of
substituents
SB 656104
pKi 8.7
Further design