Antidepressants

NEPHAR 305
Pharmaceutical Chemistry I

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Assist.Prof.Dr. Banu Keşanlı

Antidepressants
What is depression?
Depression is not a disease per se, but a clinical disorder that is manifested by a
variety of symptoms that likely represent several neurochemical/neuropathological
disorders in the brain.
Depression is a kind of mood disorder (mania, depression, anxiety) with symptoms
such as intense feelings of sadness, hopelessness, despair, lack of motivation and
inability to experience pleasure in usual activity.

“Amine hypothesis of depression”
states that depression is caused by a deficiency of monoamines, particularly
norepinephrine (noradrenaline, NE) and serotonin (5-Hydroxytryptamine, 5-HT).
Depression can be alleviated by drugs that increase the availability of noradrenaline
and serotonin.
The therapeutic efficacy of all Antidepressants is not immediate, but requires
repetitive administration over a prolonged period of time (at least 2-3 weeks before
improvement starts)

Serotonin, 5-HT Norepinephrine (NE), or noradrenalin2e

Classes of Antidepressants

1. Tricyclic anti-depressants (TCAs).
Imipramine, desipramine, nortriptyline,protryptyline, amytriptiline,
doxepin.

2. Monoamine oxidase inhibitors (MAOIs).
Isocarboxacid, phenelzine, tranylcypromine. Lithium (bipolar
disorder only)

3. Selective serotonin reuptake inhibitors (SSRIs).
Fluoxetine, sertraline, paroxetine, citalopram, escitalopram

4. Atypical anti-depressants.
New TCAs, duloxetine, venlafaxine, mirtazapine, trazodone

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Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) are chemical compounds used primarily
as antidepressants.
Increase levels of norepinephrine and serotonin by preventing their neuronal

reuptake => extended duration of post-synaptic effects

Some commonly used tricylics and heterocyclics
• Amitriptiline (Elavil®) – Metabolite is nortriptyline
• Imipramine (Trofanil®) – the prototype TCA
• Desipramine (Norpramine®)- active metabolite of
imipramine.

• Clomipramine (Anafranil®)
• Doxepin (Sinequin® )

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Tricyclic Antidepressants (TCAs)
• These are the “older antidepressants”, also referred to as the 1st generation
antidepressants
• Structurally related to the phenothiazine antipsycotics
• Tricyclic antidepressants can be either tertiary or secondary amines

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Structure Activity Relationship of Tricyclic Antidepressants
Tricyclic antidepressants have similar structures to antipsychotic
phenothiazines. However as the angle between the tricyclic rings are
different they have different activities.

Side alkyl chain and amino group do not affect the activity as much.

10 11
9 1

8 2
7 6 N 3

5 4
H

10,11-Dihidro-5H-dibenz[b,f]azepin

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Structure Activity Relationship of Tricyclic Antidepressants
• General Structure: Two aromatic rings held in skewed arrangement by a third
central ring and a three or sometimes two atom chain bonded to a aliphatic amino
group that is monomethyl or dimethyl substituted
• Central ring of the tricyclic ring of antidepressants is made of 7 or 8 atoms.
This enables tthe molecule to bend more and have a smaller angle relative to
phenothiazines.
• For example in chlorpromazine the angle between two phenyl rings is 139°,
whereas in antidepressant imipramine it is 130°.

140o 120o

N N

S

Phenothiazine (Neuroleptic) Dibenzazepine (Antidepressant)

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Structure Activity Relationship of Tricyclic Antidepressants
10 11

9 1
8 2
7 6 N 3

5 4
H

10,11-Dihydro-5H-dibenz[b,f]azepin Imipramine

• Side chain of Antidepressants are made up of 3 carbon atoms similar to
neuroleptics, in some compounds side chain has 2 carbon atoms.
Presence of 4 carbon atoms or branching decreases activity.

• Amino group is tertiary or secondary, methyl substituents on amino group
increase activity. Substituents larger than methyl such as ethyl reduce
actiity and increases toxicity.

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Structure Activity Relationship of Tricyclic Antidepressants
10 11

9 1
8 2
7 6 N 3

5 4
H

10,11-Dihydro-5H-dibenz[b,f]azepin Amitriptyline

• There may or may not be unsaturation at C10-C11 bond inBibenz[b,f]azepin and its
derivatives.

• CH10-C11 bridge can be replaced by its isosteres –CH2- N-, –CH2- O- ve –CH2- S-
groups.

• Replacing N atom at 5- position with C atom does not affect activity. 3-chloro, 10-
methyl or 10,11-dimethyl substitions improve activity.

• Removal of one of the benzene ring from the tricyclic structure makes it inactive.

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Tricyclic Antidepressants – Imipramine

Synthesis: 10,11-dihydro-5H-dibenz[b,f]azepin and 3-dimethylaminopropyl chloride
reacts in the presence of sodium amide to give imipramine.

CH3
Cl CH2 CH2 CH2 N

CH3

N NaNH2 N
H CH3

CH2 CH2 CH2 N
CH3

3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine

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Metabolism of Imipramine
• Hydroxylation takes place at 2- and10- position, hydroxylated metabolites
also show activity.
• After conjugation with glucuronic acid they are eliminated
• Another metabolic pathway is N-oxide formation.

N N
CH3 HO CH3 NH

CH2 CH2 CH2 N CH2 CH2 CH2 N
R R OH

O O
N

CH3
CH2 CH2 CH2 N

R N N
HO CH3 HO H

CH2 CH2 CH2 N
R CH

HO 2 CH2 CH2 N
R

N N
CH3 H N

CH2 CH2 CH2 N CH
R 2 CH2 CH2 N H

R CH2 CH2 CH2 N
H

Desipramine
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine 11

Tricyclic Antidepressants – Amitriptyline
Amitriptyline (Elavil), is a tricyclic antidepressant and it is the most widely used.

Synthesis: 5-Oxo-10,11-dihydro-5H-dibenzo[a,d]cyloheptadien and
3-dimethylaminopropyl magnesium bromide reacts followed by treatment with HCl
to obtain Amitriptyline after dehydration.

CH
+ 3

BrMg (CH2)3 N
CH3 CH

HO 3
O CH2 CH2 CH2 N

CH3

HCl
CH3

CH CH2 CH2 N
CH3

3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-1-amine

Metabolism of Amitriptiline
Demethylation of the side chain, hydroxylation of the ring (10- position) and
conjugation are the main metabolic pathways for amitriptiline.
Demethylated metabolite is nortriptyline which is also sold as antidepressant.

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Metabolism of Amitriptyline
H O

CH 3
CH CH 2 CH2 N CH3

CH CH CH C
3 2 H 2 N CH CH 2 CH2 NH2

O G lü.

CH CH 3
CH CH 3

2 CH2 N CH CH 2 CH 2N
CH3 H CH CH

Amitriptilin Nortriptilin 2 CH2 NH2

HO HO

CH CH 2 CHO
CH CH 3

CH CH 2 CH 2 N
CH CH 3

2 CH2 N H
CH 3

HO O H

CH CH CH
3 2 COOH

CH CH CH2 CH 2 N
3

CH CH 2 CH2 N H
CH3

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Monoamine oxidase inhibitors (MAOIs)
Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of

the monoamine oxidase enzyme family. They have a long history of use as medications
prescribed for the treatment of depression.

MAOIs increase levels of norepinephrine, serotonin and dopamine by preventing
their metabolism

Monoamine oxidase (MAO) is the principal enzyme responsible for the
metabolism of 5-HT, NE, tyramine and dopamine through deamination reaction

MAO
R CH2 NH2 + O2 + H2O R CHO + NH3 + H2O2

Because of potentially lethal dietary and drug interactions, monoamine oxidase
inhibitors historically been reserved as a last line of treatment, used only when other
classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and
tricyclic antidepressants) have failed.

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(MAOI) – Phenelzine

Phenelzine (Nardil, Nardelzine) is a non-selective and irreversible monoamine
oxidase inhibitor (MAOI) of the hydrazine class

2-phenylethylhydrazine

Synthesis : Phenylethyl bromide and hydrazine hydrate are heated in
ethanol under N2 atmosphere giving Phenelzine.

H2N NH2 . H2O
CH2 CH2 Br CH2 CH2 NH NH2

N2 / C2H5OH

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(MAOI) – Moclobemide
Moclobemide is a reversible monoamine oxidase inhibitor (MAOI)

4-chloro-N-(2-morpholin-4-ylethyl)benzamide

Synthesis: 4-Chlorobenzamide and N-(2-chloroethyl)morpholine reaction gives
moclobemide.

Cl CONH2 + Cl CH2 CH2 N O Cl CONHCH2 CH2 N O

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Selective Serotonin Reuptake Inhibitors (SSRIs)
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly

prescribed antidepressants.
Increase levels of serotonin specifically by preventing their neuronal reuptake.
Same efficacy as TCAs, but fewer side effects and not as sedating as many of

the tricylic compounds.
The SSRIs are structurally distinct form the tricyclics and are not chemically

related or chemical “look-alikes” to each other. Thus, if a patient does not respond
to one SSRI, they may respond to a different SSRI.

Fluoxetine (Prozac®) The first FDA approved and prototype SSRI (1987), the
least 5-HT selective, most widely prescribed antidepressant, sales exceed 1 bill.
$ / year.
Demethylated active metabolite, norfluoxetine resulting in considerable drug
accumulation.

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Selective Serotonin Reuptake Inhibitors (SSRIs)
– paroxetine (Paxil® ) – the highest affinity for the 5-HT transporter, no active metabolites
– sertraline (Zoloft®) – has desmethyl active metabolite
– citalopram (Celexa®) – the most selective for the 5-HT transporter, active desmethyl
metabolite
– escitalopram (Lexapro®) – the S(+) isomer of (±) citalopram, that retains the highest 5-
HTselectivity
– fluvoxamine (Luvox®) – no active metabolites, shorter half live (4-10hrs) than other SSRIs

Sertraline Fluoxetine Paroxetine

Citalopram Fluvoxamine Escitalopram 19

SSRIs – Fluoxetine (Prozac®)

Synthesis: Reduction of 1-phenyl-3-(N,N-dimethylamino)propanone
followed by acidification gives 1-phenyl-3-(N,N-dimethylamino)propyl
chloride. This reacts with sodium 4-trifluoromethyl phenolate and cyanogen
bromide to give fluoxetine.

O
CH H2 OH Cl

C CH CH 3 C
2 CH2 N 3 CH

CH CH 2 CH N H l CH
CH 3

2 CH
3 CH 2 CH2 N

3 CH3

CF3 ONa CH
CF3 O CH CH2 CH 3

2 N BrCN CF3 O CH CH2 CH2 NH CH3
CH3

KOH

(±)-N-Methyl-3-phenyl-3-[(4-trifluromethyl)phenoxy]propanamine

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SSRIs – Fluvoxamine (Luvox®)
Synthesis: 1-(4’-Trifloromethyl)phenyl-5-methoxypentanone and
O-(2-aminoethyl)hydroxylamine reaction gives Fluvoxamin.

CF C CH CH CH CH O CH H2N O CH2 CH2 NH2
3 2 2 2 2 3 CF3 C CH2 CH2 CH2 CH2 O CH3

O N O CH2 CH2 NH2

E)5-Methoxy-1-[4-trifluoromethyl)phenyl]-1-pentanon O-(2-aminoethyl)oxime

Metabolism of Fluvoxamine involves oxidation of methoxy group to
carboxylic acid and oxidative deamination.

CF3 C CH2 CH2 CH2 COOH

CF C CH N O CH2 CH2 NH2
3 2 CH2 CH2 CH2 O CH3

N O CH2 CH2 NH2
CF3 C CH2 CH2 CH2 CH2 O CH3

N O CH2 COOH

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SSRIs – Paroxetine (Paxil® )
Synthesis

CH3OOC CH3OOC ClOC
F MgBr CH3ONa (-)mentol

N CH3 F N CH3 F N CH
LiAlH SOCl 3

4 2 HBr
LiAlH4

HOCH O O
2

SOCl O OCH OCOCl
2 2 O OCH2

F N CH3
O F N CH3 KOH F NH

O ONa

(3S-trans)-(-)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine

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Atypical Antidepressants
Atypical antidepressants are not typical — they don’t fit into other classes of
antidepressants. They are each unique medications that work in different ways from
one another. These antidepressants are newer (second-generation) antidepressants
and tend to have fewer side effects than older (first-generation)

Examples:
Bupropion (Wellbutrin), Duloxetine (Cymbalta), Venlafaxine (Effexor)
Mirtazapine (Remeron), Trazodone (Desyrel)

Bupropion Venlafaxine Duloxetine Mirtazapine Trazodone

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Atypical Antidepressants – Trazodone (Desyrel)
is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class.

It is a phenylpiperazine compound.

Synthesis of Trazodone: 2-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-1,2,4-
triazolo[4,3-a]pyridin-3(2H)-one
2-Chloropyridine raects with semicarbazide in presence of catalytic amount of
acid resulting in cyclization of triazolopyridine ring. This ring then reacts with
sodium amide and 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine giving
trazodone

Cl
Cl O N

N + H2N NH C NH2 N H Cl CH2 CH2 CH2 N N
N

O NaNH2
Cl

N
N

N CH2 CH2 CH2 N N

O

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Atypical Antidepressants – Bupropion (Wellbutrin®; Zyban®)
• Bupropion is a drug primarily used as an atypical antidepressant and also effective
in treating tobacco addiction
• Bupropion is one of the most widely prescribed antidepressants,
• Structurally related to the tricyclics, but seems to have a different therapeutic
mechanism, related to altered release of NE

(±)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one

Synthesis: in two chemical steps starting from 3′-chloro-propiophenone.
The alpha position adjacent to the ketone is first brominated followed by nucleophilic
displacement of the resulting alpha-bromoketone with t-butylamine and treated with
hydrochloric acid to give bupropion as the hydrochloride salt.

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Lithium Compounds
A number of salts of lithium are used as mood-stabilizing drugs (anti-mania drug),

primarily in the treatment of bipolar disorder

Upon ingestion, lithium becomes widely distributed in the central nervous system
and interacts with a number of neurotransmitters and receptors, decreasing
norepinephrine (noradrenaline) release and increasing serotonin synthesis.

Lithium carbonate (Li2C O3)

Lithium citrate (Li3C 6H 5O 7) Lithium orotate

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