antidepressants

1. Antidepressants
1. Tricyclic antidepressants (TCAs)
2. Selective serotoninreuptake inhibitors (SSRIs)
3. Selective norepinephrine reuptake inhibitors (SNRIs)
4. Monoamine oxidase inhibitors (MAOIs)

2. TCA
N
N
R1
R2
A
B
C
1
2
3
7
5
6
8
9
10 11
General structure
 TCAs Introduced in 1957 by isosteric
replacement of phenothiazines’ “S” with a “C-
C” isostere
 This isosteric replacement also causes a
change in the numbering system
 Numbering begins at the first carbon next to
the isosteric replacement
 If there is a substituent on one of the rings,
then start numbering on that ring
N
N
CH3
CH3
H3C
CH3
N
N
S
Promazine Imipramine

3. Consequence on Ring Geometry

4. This has several consequences with respect to ring angles
 α is decreased, a β angle and γ angle is introduced causing the ring to twist
 dramatic decrease in affinity for the dopamine receptor; most TCAs are no
longer dopamine antagonists, while a few have weak dopamine antagonism
 Increased affinity for the norepinephrine, serotonin presynaptic membrane
transporter (Uptake-1)
 TCA’s work by competitively inhibiting Uptake-1 for norepinephrine and
serotonin
 TCA’s are generally more selective for the norepinephrine transporter as
compared to serotonin with the sole exception of clomipramine

5. SAR
Features common to all TCAs include: (1) A protonatable nitrogen, (2) Two
aromatic rings and (3) Approximately a 2-carbon distance between the
protonatable nitrogen and an aromatic ring
TCA Substitutions
 Not much ring substitution seen with these drugs, unsubstituted phenyl
rings are equal. Removal of a phenyl ring results in total loss of activity
 Electron withdrawing groups are not important for activity as with the
phenothiazines
 Electron withdrawing groups can change selectivity from norepinephrine
transporter to serotonin transporter and some substitutions can result in
a loss of activity (Clomipramine)
 The C10–C11 bridge can be an ethylene or vinyl with no change in
activity. In fact the C10–C11 bridge is not required; breaking the ring at
this point can retain activity (see SSRIs)

6. γ Nitrogen Substituents
1. Potency is in order: 3º > 2º > 1º amine
2. Although overall the TCAs are selective for the norepinephrine
transporter (except clomipramine) the 3° amine is more selective for
the serotonin transporter as compared to the corresponding 2°
amine; and 2° amines are more selective for NE transporter
3. 3° amines are more anticholinergic and antihistaminergic than 2°
amines. In fact more bulk on the nitrogen follows the anticholinergic
SAR
4. Ethyl or higher alkyl groups lead to a loss of activity and an increase
in toxicities. Toxicity increases with increasing chain length
5. 2o amines’ antidepressant activity followed by stimulation

7. Nomenclature of Tricyclic Ring System
N
H
1
1 H - Azepine
N
2
2 H - Azepine
H
H N
H
1
2
3
7
5
6
8
9
10 11
a
b
c
d
e
f
10,11-Dihydro-5H-dibenzo-[b,f]azepine
(as in imipramine)
O
Oxapine Cyclopheta-2,5-diene
2
6
1
1
2
3
7
5
6
8
9
2,3,6,7-Dibenzocyclohepta-2,6-diene
(as in amitriptyline)
O
1
2
3
7
5
6
8
9
11
10
a
b
c
d
e
f
Dibenz[b,e]oxepine 11[6H]ylidene
(as in doxepine)

8. TCA Classification
N
CH3
CH3
N
R
X
R X Name
H
CH3
H
H
H
Cl
Imipramine
Trimipramine
Clomipramine
N
CH3
CH3
Amitryptiline
1. Based on the middle ring, or ring B
a) Dibenzazepines: have a nitrogen at C5 (Imipramine,
trimepramine, clomipramine, desipramine)
b) Dibenzepines: no heteroatoms (Amitriptyline, nortryptiline,
protryptiline)
c) Other tricyclics: some have an O in the epine ring, or an O and
an N, an N in the eleven position, or a 6 membered middle ring
(Doxepine)
CH3
CH3
N
O
Doxepine

9. 2. Based on the substitution of the aliphatic nitrogen
a) 2o amines: differences as discussed before (Desipramine,
nortryptiline, protryptiline)
b) 3o amines: differences as discussed before (Imipramine,
trimipramine, clomipramine, amitryptyline, doxepine)
Common TCA side effects include Adrenergic, Seretonergic,
Anticholinergic, Antihistaminic, α Blocker, Quinidine-like effect
N
H
CH3
N
Desipramine
N
H
CH3
Nortriptyline
N
H
CH3
protriptyline
What angles are present here?

10. Introduction of Clomipramine in 1990
offered the psychiatrist the first drug
effectively to treat obsessive-compulsive
disorder (OCD) serious enough to interfere
with social or occupational functions

11. Miscellaneous Tricyclic Compounds
CH3
H
N
H3C
CH3
N
O
Cl
N
O
H
N
N
Maprotiline: The ethyl
bridge forms a fourth ring
(tetracyclic) resulting in
skewing of the phenyl
rings similar to the TCA’s
Doxepine: dibenzoxepine
an isostere of the TCA’s
and all else is the same as
the TC’s
Amoxapine: Related to dibenzoxazepine antipsychotic
loxapine without para methyl group which has been used in
depressed psychotics with some success. Has more dopamine
antagonistsic activity than some of the other antidepressants.
Loxapine, interestingly, has little to no antidepressant activity
CH3
N
N
N
Mirtazapine: a dibenzazepine but mechanistically is not related
to the TCA’s at all. It is thought to be presynaptic a2 adrenergic
receptor blocker that normally inhibit the release of the NE and
5-HT, thereby increasing active levels in the synapse. It also
blocks post-synaptic 5-HT2 and 5-HT3 receptors—thereby
enhance serotonergic neurotransmission while causing a low
incidence of side effects

12. Name Brand NEUI SUI Anti-DA Anti-His
amitriptyline
Elavil, Endep,
Tryptanol,
Trepiline
yes
desipramine
Norpramin,
Pertofrane
yes
imipramine Tofranil yes
nortriptyline Pamelor yes
protriptyline Vivactil yes
trimipramine Surmontil yes
amoxapine
Asendin, Asendis,
Defanyl,
Demolox,
Moxadil
yes yes yes
doxepin Adapin, Sinequan yes yes
clomipramine Anafranil yes

13. SSRIs and Other Antidepressants
 SSRIs come from breaking the TCA ring structure that decreases bulk on the
phenyl end
 The decreased bulk probably explains why these are not antagonists at the
receptors that TCAs tend to antagonize (acetylcholine, norepinephrine,
histamine)
 The group on the phenyl ring probably explains the selectivity for the
serotonin transporter
 Fluoxetine (Prozac) was the first SSRI type antidepressant introduced (1986).
Other examples include venlafaxine and duloxetine , which are SNRIs.
H3C
O
N
CH3
CH3
OH
S CH3
H
N
O
Venlafaxine
Effexor®
Duloxetine
Cymbalta®
F3C OCHCH2CH2NHCH3
Fluoxetine
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

14. Citalopram and peroxetine are potent and most specific SSRIs primarily
used to treat the symptoms of major depression, OCD, PTSD, panic
disorder, GAD, and PMDD. Citalopram is sold as a racemic mixture,
only the S-(+) enantiomer has the desired antidepressant effect. The S-
(+) enantiomer is now sold as generic escitalopram. Citalopram
metabolites desmethylcitalopram and didesmethylcitalopram are
significantly less active (although sometimes considered as active
metabolites).
O
O
O
F
NH
N
C
O
N
CH3
CH3
F
HBr N
CH3
C
O CH3
F
N
O
O
HO
HO
Paroxetine
(Antidepressant; SSRI) Citalopram Hydrobromide (Celexa)
(Antidepressant; SSRI)
Escitalopram Oxalate (Lexapro)
(Antidepressant; SSRI).

15. SSRI Related Compounds
 Atomoxetine and Reboxetine are selective norepinephrine reuptake inhibitors
(SNRIs) which are very selective for inhibiting the norepinephrine reuptake
transporter (Be careful, SNRI has also been used to stand for Serotonin
Norepinephrine reuptake inhibitor such as venlafaxine)
 These drugs lack a strong electron withdrawer on the phenyl ring that decreases
selectivity for the serotonin transporter
 They retain a similar side effect profile except adrenergic side effects (has more
adrenergic side effects than SSRIs)
 Atomoxetine is used in the US for ADHD and Reboxetine is used in Europe for
depression
 These drugs don’t have serotonergic side effects and, thus, decrease the risk
for serotonin syndrome
CH3
H
N
CH3
O
Atomoxetine
Strattera® CH3
O
O
NH
O
Reboxetine
Vestra®

16.  Basic, the cyclopropane ring is completely rigid and
will dominate the 3-D structure of the drug
 Racemic; however, the 'active' d-isomer having a
longer half-life than the 'inactive' l-isomer. The
approved drug is the Hydrochloride salt
 SNRI in 3:1 ratio and used for the treatment of
clinical depression (serotonin) and fibromyalgia (NE)
 Well absorbed after oral dosing (bioavailability of
85%), meals do not have an influence on the rapidity
and extent of absorption
 Conjugated to the inactive glucuronide and excreted
in the urine as unchanged drug and conjugate. Only
traces of active metabolites are found. Enzymes of
the CYP class do not play a role in the metabolism of
Milnacipran so that the risk of interactions with drugs
metabolized by CYP enzymes is minimal.
New Molecular Entity in 2009: Milnacipran
NH2
O N CH3
CH3
MILNACIPRAN

17.  Triazolopyridines contain a fused triazole ring and a pyridine ring, e.g.,
trazadone, which have a complex pharmacology
 Nefazodone is an analog
 The N closest to the triazole ring and the phenyl ring on the end opposite the
triazolopyridine ring structure are the parts that interact with the receptor
 These drugs are selective inhibitors of the serotonin transporter.
 They are not considered to be SSRIs due to a different side effect profile
 They are also good a blockers, and 5-HT2A antagonists
H3C
O Cl
N
N
O
N
N
N
Nefazodone
Serzone®
(discontinued due to liver toxicity) Cl
N
N
O
N
N
N
Trazadone

18. MAOIs
O
NH2
N
H
N CH3
CH3
H
N
N
H
O
N
Isoniazide
Antitubercular but too polar
Iproniazide
Antitubercular but CNS stimulant
Which later shown to be MAOI
resulting in  NE & 5-HT
New antidepressant introduced but
withdrawn due to liver toxicity, however,
increased interest on hydrazines and
hydrazides for antidepressants
H2N NH2
 Thus MAOIs based on the hydrazine molecule have been extensively studied.
Hydrazine, itself, has no MAOI activity
 Must have a free amino at one end to be active; a protonatable terminal N is
necessary; those without a terminal N are prodrugs and must be bioactivated
 Must have at least one free hydrogen on each nitrogen
 Adding an alkyl group to one nitrogen of hydrazine confers MAOI activity: Ethyl is
the most potent of the series methyl, ethyl, propyl, etc. Branching with a methyl
group does not affect potency
hydrazines

19. Ring Additions & Disubstiturions
Ring Addition
 Adding a phenyl ring produces a compound with no MAOI activity
 Adding a benzyl ring confers good activity, adding a phenethyl (phenyl
ethyl) ring is even more potent
 More closely approximates norepinephrine, serotonin and dopamine, etc
Disubstitution
 N,N disubstitution on one end decreases, or loses, potency
NH2
H
N
Phenelzine

20. Hydrazides & Mechanism
CH3
N O
O
H
N
N
H
CH3
CH3
H
N
N
H
O
N
Hydrazides: hydrazine with one nitrogen forming an amide, e.g., Iproniazid and
isocarboxazide
 These drugs have lipophilic substituents that allow them to cross the
BBB, where they are hydrolyzed to the active species. This increase
the potency by allowing more drug to reach the site of action
 Note isoniazide is a hydrazide but is not bioactivated
 Mechanism of Action - MAOIs covalently bind MAO, irreversibly
inhibiting the reaction.
Isocarboxazide Iproniazid
NH2
H
N
Phenelzine
An effective mechanism-based antidepressant agent. It is
presumably oxidized to diazene (HN=NH) (which can then break up
into molecular nitrogen, a hydrogen atom), and a phenethyl free
radical that would be the active species in irreversible inhibition

21. Competitive MAOIs
 The present clinically useful irreversible MAOIs are mechanism-based
as they form reactants that covalently bond the enzyme or its cofactor
 Thus they may continue their action up to 2 weeks after administration
is discontinued
 The harmala alkaloid harmaline and harmine are competitive inhibitors
of MAO and are CNS stimulants
 Moclobemide has received considerable attention. It is an effective
antidepressant without producing hypotensive crisis which is a
reversible inhibitor of MAO-A and permits metabolism of dietary
tyramine, however, caution is still needed to avoid excessive intake (of
cheddar cheese, feva beans)
O N CH2CH2N
H
C
O
Moclobemide

22. Miscellaneous MAOIs
► Tranylcypromine
► The distance from the phenyl to the amine is closer to
norepinephrine
► The cyclopropyl group is very strained (reactive) and alkylates
the enzyme
► The trans isomer is more potent than the cis isomer
► The ring is more unstable and binds the enzyme better
► (-)-Selegiline
► Has an acetylene functional group that is unstable
► Results in covalent bond to the enzyme
► Part of its metabolic fate is N-dealkylation to
methamphetamine
► Selegiline is the (–) isomer and so it forms (–)
methamphetamine not the active (+) form as shown
► Selective MAO-B irreversible inhibitor (at lower doses)
CH
C
CH3
CH3
N
CH3
N
H
CH3
NH2

23. Study Guide
 What is the consequences of ring geometry on activity with the isosteric
replacement of S with -CH2CH2-
 What are the common structural features of TCAs
 What are the effect of ring substitution by an electron withdrawing group on
TCAs?
 Activity towards NE vs 5HT transporter system of 1o, 2o and 3o amines on the
side chain.
 Classes of TCAs based on both ring system and side chain amine with
examples. Also know the angles present in each class of compounds.
 Structures and activity of misc.: maprotiline, doxepine, amoxapine, mirtazapine.
 What is SSRI and SNRI? How can you generalize from structures? How was
SSRI developed from TCAs? Know all about milnacipram. Is trezadone an
SSRI? Why or why not?
 What are different classes of MAOIs? SAR of hydrazine derivatives. What are
selective MAO-A and MAO-B inhibitors?