Lecture for Med chem/B.Pharm of Purnbanchal University, Nepal

1. Antidepressants
Depression is one the most treatable
mental illness*
*Foye's principle of medicinal chemistry

2. Depression
It is a mental illnesses characterized by pathological
changes in mood (in contrast schizophrenia is disorder
in thought)
Two types of mood disorders
1) Unipolar disorders
• Depression – lacking enthusiasm
• Mania – excessive or unreasonable
enthusiasm
2) Bipolar disorder (Alteration between manic-
depressive phase)

3. What does CLINICAL Depression feel
like?
Confessions of depressed people
“an empty hole (in ur heart)”
“ life not being worth anything”
“don’t feel sad or happy, feel numb”
“can’t make simple decision, can’t communicate”
“feels tiring”
“like the whole world is in your shoulder”
https://www.youtube.com/watch?v=K-F9f1nJAW0

4. How severe can depression be
physiologically?
• Depression isn’t just a psychological state that
can drive to suicide. It has physiological
consequences too that can interfere with quality
of life
• Insomnia (lack of sleep)
– Weakens immune system, fatigue
• Increases pain perception
• To suppress depression people do
– Excessive eating  obesity related heart problem
– Excessive alcohol  liver damage and withdrawal
symptoms

5. Cause of Depression
• Like schizophrenia , the exact cause is unknown
• 1) Monoamine Hypothesis : The accepted cause is deficiency
of Neuro transmission by biological amines Nor-adrenaline (NE)
and Dopamine (DA) and Serotonin(5HT) in the CNS
• Evidence – Reserpine, which has antihypertensive actions due
to its ability to deplete catecholamines (DA and NE) and 5HT
from peripheral sympathetic nerve endings, caused depression
• Drugs that promote catecholamines and serotonin in the
synapse relieved depression
– MAOI – block metabolism of DA and NE
– TCA – block reuptake of NE and 5HT

6. • However not all monoamine reuptake inhibitors are
anti-depressant eg Cocaine is a potent inhibitor of
noradrenalin and dopamine reuptake. However it is not
an anti-depressant but an addictive
2) Receptor Sensitivity Hypothesis
To compensate the deficiency of NE and 5HT in the
synapse, the post synaptic receptors become
hypersensitive to these neurotransmitters and also
they increase in number. This explains the delay in
anti-depression therapy where drug effects are seen
only after few weeks. The drugs need to first increase
the NE and 5HT in synapse enough to normalize the
hypersensitivity and increased number of their
receptors and then only they start to show anti-
depression action.

7. *Foye's principle of medicinal chemistry

8. Antidepressants Classification
1) Tricyclics and Tetracyclics (TCA)
Imipramine Doxepin Amoxepine
Amitriptyline Nortriptyline
2) Monoamine Oxidase Inhibitors (MAOIs)
Phenelzine Moclobemide
3) Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine
Sertraline Citalopram
4) Dopamine and Norepinephrine Reuptake Inhibitor (DNRI)
Bupropion
5) Mood stabilizer- Lithium Carbonate

9. There are 5 Gen of antihistamines
Generation Property eg
1st Effect various NT with no selectivity TCA, maprotilline
2nd No anticholinergic action
Weak antihistaminic and adrenolytic
action
mianserine, mirtazapine,
trazodone
3rd Selective inhibition of NE,DA or 5HT
does not affect muscarine, histamine and
adrenergic cerebral systems
SSRI, ipsapirone,
viloxazine, reboxetine,
bupropione
4th Selective (5HT and NE) or (DA and NE) milnacipran, befloxatone
5th Selective 5HT and NE and DA venlafaxine, cericlamine
Ref: Cesk Psychiatr.1994 Feb;90(1):3-19.

10. Discovery of TCA’s
•Chlorpromazine (CPZ) was the first anti-phycotic drug.
•TCA’s were the first anti-depressents. They were accidentally discovered while
searching for better derivative of CPZ. Hence they appear similar in structure
Imipramine
Amitriptyline
Protriptyline
Doxepin
Chlorpromazine
Maprotiline

11. • TCA’s refer to a general structural class seen in
– NE and 5HT Selective Reuptake Inhibitor (NSRI)
• Contains 3o terminal amine group
– Selective NE Reuptake Inhibitor (SNRI)
• Contains 2o terminal amine group
• TCA’s generally have a wide side effect profile due
to potency for other receptors such as
– muscarinic
– histamine
– alpha1-adrenergic
– sodium channels (causes cardiotoxicity)
• Thus selective inhibitor such as Serotonin/
Noradrenaline Reuptake Inhibitors (SSRI/SNRI)
are preferred

13. SAR of TCA’s
1) It consist of 3 ring in 6-7-6 or 6-6-6 format,
with two phenyl rings fused by a central 6 or 7
membered ring that can be homocyclic or
heterocyclic. The central ring can be bridged
to form a tetracyclic rings
Homocyclic (contains only
carbon in central ring)
Heterocyclic (contains other
atoms than carbon like N/O/S
in central ring)
Imipramine
Amitriptyline
Maprotiline

14. • They differ form antipsychotics in that instead
of a sulphur, the rings are connected by two
carbon units
Imipramine
Anti-depressent
Promazine
Anti-psycotic
• The three rings do not contribute to receptor
binding but are responsible for various CNS side
effects due to high lipophilicity. (Thus this
feature is absent in later inhibitors)

15. 2) The methylene linker to the terminal amine must be
3 carbon units and can side chain can be attached by
any carbon on the central ring
It can be saturated or unsaturated.
It should not be branched
Cis form is potent than trans form
ImipramineAmitriptyline
Saturated (no double
bond) 3 carbon linker
Unsaturated (has
Double bond)3
carbon linker
Amoxepine has terminal
amine attached to a
different carbon

16. Imipramine
Branching reduces potency
of Trimipramine by 100
times relative to Imipramine
Cis form is more potent
than trans

17. 3) Substituting a halogen or CN (cyano) group in
3 position of either phenyl ring increase
selectivity for 5HT transportor
Clomipramine
Selectivity Ratio of 5HT/NE
132
Imipramine
Selectivity Ratio 5HT/NE
26
Clomipramine is considered the most powerful antidepressant ever made

18. 4) The terminal group has to be a amine and it
controls pharmacodynamics
Secondary amine group have more potency to NE transportors
Tertiary amine group are non-selective to NE or 5HT transporter’s
potency
1 Des-
ipramine
More NE
2 Ipramine NE/5HT
3 Nortryptilli
ne
More NE
4
Amitrpytilli
ne
NE/5HT

19. Imipramine
It is a tricyclic antidepressant (TCA) of the
di-benzazepine group. It was the first compound
of it’s type.
It is used in the treatment of
– Depression
– Bedwetting
• Within the body, Imipramine is demethylated to
desipramine, another TCA.
• MOA: It blocks transporters of 5HT and NE which prevents
their reuptake from the synapse and thus prevents
depression in agreement to monoamine hypothesis

20. Doxepin
• It is a TCS of dibenzoxepine group with an unsaturated heterocyclic central
ring containing oxygen
• Two isomers are possible and is marketed in 85:15 mixture of Trans : Cis
• Cis form inhibits reuptake of 5HT and Trans form inhibits reuptake of NE
• The isomers do not differ in bioavailability but the Trans is metabolized
to a larger degree such that the demethylated (3o amine converts to 2o
amine by loss of a methyl group) metabolite of both trans and cis exist
in 1:1 ratio
It is used in the treatment of Depression and also Itch and insomnia
MOA: It blocks transporters of 5HT and NE which prevents their
reuptake from the synapse and thus prevents depression in
agreement to monoamine hypothesis

21. • is a TCA of the dibenzoxazepine group with unsaturated
heterocyclic central ring that has both N and O and the
terminal amine is with a cyclic piperazinyl ring
• Comparatively it has a faster onset of action (four to
seven days instead of 2-3 weeks) and shortest
elimination (8 hr)
• It has anti-depressive and anti-psycotic property
• Used in major depression and in delusional depression
• MOA: It blocks transporters of 5HT and NE which
prevents their reuptake from the synapse and thus
prevents depression in agreement to monoamine
hypothesis
Amoxepin

22. Amitriptyline
• It is a TCA of the dibenzocycloheptene group
and has unsaturation in both the central ring and propyl
linker
• It is metabolized into Nortriptyline by demethylation and
it also is a TCA
• It is used in
– Major Depression
MOA: It blocks transporters of 5HT and NE which prevents
their reuptake from the synapse and thus prevents
depression in agreement to monoamine hypothesis

23. Nortriptyline
• It is a TCA of the dibenzocycloheptene group
and has unsaturation in both the central ring and
propyl linker
• It is a major demethylated metabolite of
Amitriptyline
• It is used in
– Depression
– bedwetting and neuropathic pain
MOA: It blocks transporters of 5HT and NE which
prevents their reuptake from the synapse and thus
prevents depression in agreement to monoamine
hypothesis

24. SSRI (Selective Serotonin Reuptake Inhibitors)
Discovery
• The need for SSRI was due to high side effect
profile of TCA’s which had potency for various
receptors other than NE and 5HT transporters
• It was discovered that the antihistaminic drug
Pheniramine was also a selective inhibitor of 5HT
transporter without any cardio toxic effects
• Thus structural manipulation was done on
Pheniramine to result the first SSRI- Zimeldine
• SSRI and SNRI represent 2nd Gen Antidepressents

25. Antihistaminic Antidepressants
Zimeldine was withdrawn from
market due to Gullian Barre symptom
(immune system attacking nerves)
Further research lead to discovery of Fluoxetine.
Fluoxetine and it’s derivatives are successful SSRI

27. • SSRI have many therapeutic uses (this reflects
the involvement of 5HT in many physiologic
process)
– depression,
– OCD, obesity, personality disorder , anxiety
– panic disorder, migraine, alcoholism, rheumatic
pain, premenstrual disorder, bulimia (over eating)
• They are claimed to be better tolerated than
TCA’s with fewer side effects
• They are expensive and this has lead to
patient again falling into depression because
they could not continue with this drug
• SSRI have a history of increased risk of
suicide for unknown reasons

28. • Selectivity and potency for 5-HT uptake do not
coincide
• Citalopram is the most selective 5-HT-uptake
inhibitor, whereas paroxetine is the most potent
• SSRI are not perfect!
• Side effects include nausea, diarrhea, anxiety,
agitation, insomnia and sexual dysfunction
• But no anticholinergic or cardiotoxic effects like
TCA’s

29. SAR of SSRI
• Mono susbtitution in para position of phenoxy
group by electron withdrawing group results
gain in 5HT selective inhibition
• But
– bi-substitution
– or mono-substitution at other places or
– use of electron donating group
• causes loss in selective inhibition
CF3 is mono-subs in
para position

30. • Introducing ring in the fluoxetine derivatives
maintains selectivity for 5HT transporter but
lowers the potency, except in paroxetine
which is more potent than fluoxetine
• The amine group shows maximum potency
when in 2o form ie 3o amine reduce potency
for 5HT transportors

31. NOTE
GENERAL Effect of Amine on
potency
Amine Potency
TCA’s Secondary NE
Tertiary NE/5HT
SSRI Secondary 5HT
Primary Reduced 5HT
Tertiary Reduced 5HT

32. Locate chiral carbons
H
N
Cl
Cl
Fluoxetine
Sertraline
Citalopram

33. Fluoxetine
• It is an antidepressent of the SSRI class
• The S enantiomer is 100 times more selective but R
enatiomer is 8 times more potent and has longer
duration of action (ie selectivity and potency do not
correlate for SSRI)
• It’s N-demethylated metabolite, NorFluoxetine has
weaker activity but is responsible for it’s long half life
• Uses - major depressive disorder, OCD, post-traumatic
stress disorder, premenstrual disorder, bulimia
nervosa, panic disorder, and obesity
• MOA- It selectively blocks presynaptic 5HT transporter
which inhibits reuptake of 5HT leading to
antidepressent effects in accordance to monoamine
hypothesis

34. Sertraline
• It is an antidepressent of the SSRI class
• It has two chiral centers and only the S,S diastereomer
is active
• It’s N-demethylated hepatic metabolite, NorSertraline,
is 5-10 times weaker than sertraline
• Uses - Major Depression, OCD, body dysmorphic
disorder, post-traumatic stress disorder, premenstrual
disorder, panic disorder and social phobia
• MOA- It selectively blocks presynaptic 5HT transporter
which inhibits reuptake of 5HT leading to
antidepressent effects in accordance to monoamine
hypothesis

35. Citalopram
• It is an antidepressent of the SSRI class
• Only the S enantiomer is active (27 times more active
than R)
• Citalopram is the most selective 5-HT uptake inhibitor
but not the most potent
• Unlike other SSRI, it doesn’t undergo 1st pass
metabolism
• It’s N-demethylated metabolite, desmethylcitalopram
retains 50% potency
• Uses: Major depressive disorder, chronic depression,
OCD, anxiety, panic disorder, premenstrual disorder, Body
dysmorphic disorder
• MOA- It selectively blocks presynaptic 5HT transporter
which inhibits reuptake of 5HT leading to antidepressent
effects in accordance to monoamine hypothesis

36. Bupropion
• It is an amino ketone antidepressent of the DNRI class
• The tertiary butyl group prevents N-demethylation like
in other antidepressents
• It’s property to antagonize nicotine at therapeutic doses
is used to combat smoking withdrawal symptoms
• Uses- Depression, 2nd line treatment in Smoking
cessation
• MOA – It primarily inhibits pre-synaptic DA and, to a
lesser extent, NE transporters and increases their levels
in the synapse which results antidepressant effect in
accordance to monoamine Hypothesis

37. Lithium Carbonate (Li2CO3)
• Lithium (Li) is a simple monovalent cation, which
as a salt, carbonate or citrate, is used in the
– treatment of mania
– in the augmentation treatment of depression
– and in the prophylaxis of bipolar disorder
• It is the only drug that has shown to reduce
suicidal tendency in depression
Ref: Can J Psy chi a try, Vol 48, No 7, August 2003
• But it is not without side effects
• EPS, Hair loss, Hypothyroidism
• Nausea, Vomitting, Leukocytosis, Dry mouth,
increased thirst, Decreased memory

38. • They were used since 1894 for depression and
is very effective but we don’t yet know the
actual MOA
• The postulated MOA is Lithium in therapeutic
concentrations blocks the activity of the
enzyme, inositol-1-phosphatase, resulting in a
depletion of neuronal inositol and ultimately
decrease levels of phosphatidylinositol
biphosphate(PIP2) and it’s 2nd dary messenger
IP3 and DAG

39. Thank You

40. There are 5 Gen of antihistamines
Gener
ation
Property
1st Effect various NT with no selectivity TCA, maprotilline
2nd No anticholinergic action
Weak antihistaminic and adrenolytic action
mianserine, mirtazapine,
trazodone
3rd Selective inhibition of NE,DA or 5HT
does not affect muscarine, histamine and
adrenergic cerebral systems
SSRI, ipsapirone, viloxazine,
reboxetine, bupropione
4th Selective (5HT and NE) or (DA and NE) milnacipran, befloxatone
5th Selective 5HT and NE and DA venlafaxine, cericlamine