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Antidepressants
• Understand the meaning of depression
• Classify the different antidepressants
according to mode of action
• Identify general chemical structure of
antidepressants
• Distinguish between different
pharmacological classes according to
structure features.
• Predict different metabolic pathways
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2. Depression
• Depression is a state of low mood and
aversion to activity, feeling "depressed" is
often synonymous with feeling sad.
• Types of depression:
Major depression
Bipolar disorder.
Seasonal depression.
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Antidepressants
• An antidepressant is a Psychiatric medication
used for alleviating depression.
• Current hypothesis regarding the causes of
depression support the role of
neurotransmitters serotonin (5-HT) and
norepinephrine (NE) in depression .
• Antidepressants therapy is centered around
monoamine reuptake inhibitors , Monoamine
oxidase inhibitors , and receptor antagonists
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4. Monoamine reuptake inhibitors
Norepinephrine Seretonin
Reuptake Inhibitors (NSRIs)
Tricyclic antidepressants
(TCA)
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MOA: Antidepressants act by their ability to
inhibit monoamine transporter mechanisms
in the brain.
5. SAR of Tricyclic Antidepressants
TCA have in common a tricyclic ring structure
consisting of a central six membered or more
commonly a seven –membered ring flanked by two
benzene rings held in a skewed arrangement. This
tricyclic bulky structure lacks coplanarity
N
N
1
2
3
4
5
6
7
8
9
10 11
R
5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine HCl
Imipramine R=CH3
Desipramine R=H
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Ring Nitrogen atom is not required for
antidepressant activity, replacement with sp3 or sp2
carbon enhances antidepressant activity.
The side chain must be three carbon atoms ,either
saturated (propyl) or unsaturated (propylidine)
NH
Protriptyline
SAR of Tricyclic Antidepressants
N
N
1
2
3
4
5
6
7
8
9
10 11
R
Imipramine
Amitriptyline
10
6. • For TCA with six membered central rings , If
the central ring is capable of aromatization, by
oxidation for example, to afford a completely
planar structure, the resulting compound is
inactive.
• If aromatization can be prevented,
antidepressant activity is retained.
• Maprotiline ( Ludiomil) is an example of a
tricyclic agent where aromatization is
prevented by introduction of an alkyl bridge.
SAR of Tricyclic Antidepressants
NH
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SAR of Tricyclic Antidepressants
The tricyclic system is generally attached to a basic
terminal amine by a three carbon chain. The carbon
chain could not be shortened to two carbon atoms.
Branching of the propyl side chain markedly decrease
the affinity to both SERT and NERT
The Z (cis ) geometry for the propylidine gp in Chiral
TCA appear to be important for the transporter
selectivity and affinity (Doxepin???).
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7. Doxepin
• Doxepin is a tricyclic antidepressant (TCA). It is approved
for the use in treatment of major depression and
insomnia. Doxepin is also utilized as part of the treatment
of chronic urticaria and in pain management.
• Doxepin is shown to inhibit the reuptake of noradrenalin
and serotonin. The reuptake inhibition of dopamine is
very weak. Doxepin's metabolite desmethyldoxepin
(nordoxepin) has also antidepressant effects.
• Doxepin binds strongly to the histamine H1 and H2
receptors. Its selective histamine antagonist function is
responsible for the drug's sleep-promoting properties.
• Doxepin also acts antagonistic on 5-hydroxytryptamine
(serotonin) receptors, alpha 1 adrenergic receptors and
muscarinic cholinergic receptors.
• Conventional doxepin preparations are a mixture of Z
(cis)- and E (trans)i-isomers in a ratio 15:85.
• The E-isomer is more active as a serotonin reuptake
inhibitor, while the Z-isomer shows greater activity as a
sedative.
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The terminal amine is typically a secondary or tertiary
amine, also the amine can be part of an alicyclic ring.
In general, tertiary amines are more nonselective with
respect to inhibition of 5-HT and NE reuptake, whereas
the secondary amines are typically more selective at
inhibiting NE reuptake
Introduction of electron withdrawing group (e.g. Cl)in
amoxapine (dibenzoxazepine TCA) enhances
antipsychotic profile of the TCA agent.
Secondary amines (Amoxapine)
show a greater antidepressant
profile than that of tertiary amines
Antidepressant
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8. The terminal amine is typically a secondary or tertiary
amine, also the amine can be part of an alicyclic ring.
In general, tertiary amines are more nonselective with
respect to inhibition of 5-HT and NE reuptake, whereas
the secondary amines are typically more selective at
inhibiting NE reuptake
Introduction of electron withdrawing group (e.g. Cl)in
amoxapine (dibenzoxazepine TCA) enhances
antipsychotic profile of the TCA agent.
Secondary amines (Amoxapine)
show a greater antidepressant
profile than that of tertiary amines
Antidepressant
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• In general, with the exception of the secondary
amine metabolites of N,N-dimethylaminoTCAs, the
metabolites are usually less active or inactive as
antidepressants.
SAR of Tricyclic Antidepressants
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9. Adverse effects of antidepressants
• The tricyclic structure is not associated
with affinity to any particular receptor but
rather contributes to multiple CNS
pharmacodynamic (adverse) Effects
because of increased lipophilicity
• They not only block The reuptake of 5HT
&NE but also block muscarinic
receptors(anticholinergics),
α1 adrenergic receptors,
H1receptors(antihistamine),
and sodium channel
N
N
1
2
3
4
5
6
7
8
9
10 11
R
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10. Imipramine & Desipramine
• Imipramine (Tofranil) Desipramine
N
N
1
2
3
4
5
6
7
8
9
10 11
N
NH
1
2
3
4
5
6
7
8
9
10 11
•Imipramine may be considered as the parent compound
of TCA. It is also close relative to the antipsychotic
phenothiazines (isostoric replacement 10-11 bridge with
sulfur).
• Metabolic deactivation proceeds mainly by oxidative
hydroxylation in the 2-&10- position followed by
conjugation.
Metabolic N-demethylation gives nor- (or des-) imipramine
which is SNRI (active metabolite).
19
Tricyclic antidepressants
• Clomipramine(Anafranil)
• It is 50 times more potent than imipramine, it is the most
powerful antidepressant
• protonated amino and unshared electrons of the
chlorosubstituent might stabilize the ß-arylamine like shape
and give more efficient competition for the transporter.
• The chloro substituent could increase the potency by
increasing the distribution to CNS.
. Used for obsessive compulsive disorder (OCD)
N
N
1
2
3
4
5
6
7
8
9
10 11
Cl
20
11. Tricyclic antidepressants
• Amitriptyline (Elavil,Tryptizol)
• Metabolism:
• Active metabolite(10–hydroxy metabolite)
• Amitriptyline is one of the most anticholinergic and
sedatives TCA
N
NH
Nortriptyline
(Aventyl)
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Tricyclic antidepressants(cont.)
• Since Amitriptyline lacks electron enriching
nitrogen atom of imipramine, metabolic inactivation mainly
proceeds via benzylic oxidation at position 10- and not 2-
position.
• Metabolic N-demethylation occurs to give
nortriptyline which has a less anticholinergic, less sedative
and more stimulant action than amitriptyline.
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13. Norepinephrine & Seretonin
Reuptake Inhibitors
• Venlafaxine (Effexor)
• It is a non tricyclic NET&SERT
inhibitor
• It is a methoxyphenylethylamine
• Its major active metabolite is o-
demethylated product
• Its minor inactive metabolite is N-
demethylated product
• Venlafaxine & its active metabolite have
dual MOA with preferential affinity to 5HT
reuptake and weak Inhibition of NE (30:1)
Venlafaxine
NorepinephrineSerotonin Reuptake
Inhibitors (NSRI)
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Duloxetine (Cymbalta)
14. 2- Selective seretonin
reuptake inhibitors
(SSRIs)
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2-Selective Seretonin Reuptake Inhibitors
(SSRIs)
• Citalopram (Cipram/Celexa):
Very selective SERT inhibitor
Monodemethylated metabolite exhibits 50% the
potency of citalopram
Ether function is essential
Used as racemic mix,but
the activity resides to S(+) isomer
• Isosteric replacement of benzoisofuran
With benzoisothiophene
yields Talsupram (NET inhibitor)
• Escitalopram (Lexapro)
S enatiomer of citalopram binds with high affinity &
selectivity to SERT
O
N
F
C
N
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15. 2-Selective Seretonin Reuptake Inhibitors
(SSRIs)
• Fluoxetine (Prozac)
N-methyl-3-phenyl-3-
[4-(trifluoromethyl) phenoxy]-
propan-1-amine
Monosubstitution in 4 position of phenoxy gp with
electron withdrawing gp (CF3)results in selective
inhibition of 5HT
Disubstitution 2,3 or 3,4 results in loss of SERT
selectivity
Metabolism : N-demethyl compound(Nor fluoxetine)is
as potent as the parent compound and more
selective SERT inhibitor
O
HN
CF3
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SSRIs(Fluoxetine cont.)
• Both enantiomer(R,S) display
similar affinities for SERT .
• The S- enantiomer is 100 times more selective
for SERT rather than NET
• If the para substituent is
moved to the ortho
position and substituted
by methoxy group,
a SNERI is obtained as in Nisoxetine.
• Fkuoxetine is Used in ttt of bulimia nervosa nisoxetine
17. Monoamine Oxidase Inhibitors
MAO is a family of flavin containing enzymes located primarily in
the membranes of mitochondria.
These enzymes inactivate biogenic amines as NE, DA, 5-HT,
tryptamine and tyramine by conversion of these amines to
aldehydes which are subsequently oxidized to acid or reduced to
alcohol. R-CH2-NH2 + O2 + H2O R-CH=O + NH3 + H2O2
MAO enzymes may be subdivided into two isoenzymes.
MAO-A that preferentially metabolizes 5-HT & E & NE
MAO-B preferentially degrades phenethylamines.
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Monoamine Oxidase Inhibitors( MAOIs)
• MAOI have the problem of inhibiting the MAO in the
brain (MAO-B) and also in the liver (MAO-A) thereby
allowing dietary pressor amines that would normally
be inactivated to exert their effects.
• Severe hypertensive responses, sometimes fatal, have
followed ingestion of foods high in pressor amines.
• MAOI produce irreversible inhibition that lasts for one
to two weeks after the last dose by a mechansim
discussed here after.
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18. Members of MAOI
First generation MAOI; Irreversible, Nonselective
Tranylcypromine sulfate (Parante)
Pargyline Hydrochloride (Eutonyl)
Second Generation MAOI : Irreversible, Preferential
Seligiline
Third Generation MAOI: Reversible, Preferential
Moclobemide
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First generation
MAOI
(Irreversible,
Nonselective)
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19. Tranylcypromine Sulfate
(Parante)
• It was designed as cyclopropyl analogue of
amphetamine
• It is nonselective irreversible MAO inhibitor
• Metabolism:- Aromatic hydroxylation
- N-Acetylation
NH2
()-Trans-2-phenylcyclopropylamine Sulfate
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Second generation
MAOI
(Irreversible,
Preferential)
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20. Seligline (l-Deprenyl)
• . Deprenyl has the advantage of sparing liver
MAO-A and thereby, avoid the “Cheese effect” of
tyramine and other dietary pressor amines
• EMSAM the first skin (transdermal) patch for use in
treating major depression. The once a day patch
works by delivering selegiline, or MAOI, through the
skin and into the bloodstream.
CH3
N
H3C
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Seligline (l-Deprenyl)
• Metabolism:
CH3
N
H3C
Desmethylseligline l-metamphetamine
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