Antidepressants
Morten Grøtli
Department of Chemistry and Molecular Biology
Email: (grotli@chem.gu.se)
Useful reading (refer to Foye’s 7th ed)
• Chaper 18 , page 570
Neurotransmitter deficiency
syndroms and their interactions
Monoamine hypothesis
Serotonin nurotransmission
Norephinephrine
nurotransmission
Types of antidepressive drugs
Antidepressive
drugs
Monoamine
reuptake
inhibitors
Selective
Nonselective
Monoamine
oxidase
inhibitors
Miscellaneous
Selectivity ratios for reuptake inhibitors
Norephinephrine reuptake
Serotonin reuptake
TCA
Tricyclic antidepressants
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
General structure
If there is a substituent on one of the rings, then start
numbering on that ring
Tricyclic antidepressants
Tricyclic antidepressants

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 (reuptake)

TCA’s work by competitively inhibiting reuptake for norepinephrine and
serotonin

TCA’s are generally more selective for the norepinephrine transporter as
compared to serotonin with the sole exception of clomipramine
Tricyclic antidepressants
Tricyclic antidepressants
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)
γ Nitrogen Substituents
Tricyclic antidepressants
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.
Tricyclic antidepressants
1.
Based on the middle ring, or ring B
Dibenzazepines: have a
clomipramine, desipramine)
nitrogen
at
C5
(Imipramine,
trimepramine,
Dibenzepines: no heteroatoms (Amitriptyline, nortryptiline, protryptiline)
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)
Tricyclic antidepressants
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
What angles are present here?
Metabolism of clomipramine
Tricyclic antidepressants
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
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 5HT2
and
5-HT3
receptors—thereby
enhance
serotonergic
neurotransmission while causing a low incidence of side effects
Metabilisme of mirtazapine
Selective norepinephrine reuptake
inhibitors (SNRI)
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 decrease the risk for serotonin syndrome
Metabolism of R-atomoxetine
Selective serotonin reuptake
inhibitors (SSRIs)
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.
Venlafaxine
Duloxetine
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Phenoxyphenylalkylamine selective
serotonin reuptake inhibitors (SSRIs)
Derivatives of fluoxetine
Serotonine reuptake transporter
(SERT) affinity
Metabolism
Phenylalkylamine SSRIs
The metabolism of sertraline
Miscellaneous SSRIs
Non-tricyclic reuptake inhibitors
Metabolism of venlafaxine
Metabolism of duloxetine
Dopamine and norepinephrine reuptake
inhibitors; Bupropion
Dopamine and norepinephrine
reuptake inhibitors
Serotonin
reseptor
modulators
Metabolism of trazodone
Metabolism of aripiprazole
MAOI antidepresants
MAOI antidepresants
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
hydrazines

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
MAOI antidepresants
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

Phenelzine
N,N disubstitution on one end decreases, or loses, potency
MAOI antidepresants
Hydrazides: hydrazine with one nitrogen forming an amide, e.g., Iproniazid and
isocarboxazide
Isocarboxazide
Iproniazid
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.
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
Competitive MAOIs
MAOI antidepresants
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)
MAOI antidepresants
►
►
NH2
►
►
►
CH3
CH
N
C
CH 3
CH3
N
H
CH3
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)
Lithium ion suppresses inositol
triphosphate signaling
Intracellular phosphatidylinositol signaling
pathway and site of action for lithium
Agomelatine
The first approved antidepressant to incorporate a non-monoaminergic
mechanism of action.
Agomelatine
The first approved antidepressant to incorporate a non-monoaminergic
mechanism of action.
Questions
1. Strukturerna för två läkemedel visas i Figur 2. Föreslå trolig
farmakologisk effekt för varje läkemedel.
2. Läkemedel C kan metaboliseras till flera metaboliter. Rita och
förklara hur tre olika metaboliter kan bildas.
3. D metaboliseras i huvudsak i levern, till den aktiva metaboliten
X. Rita S-isomeren av metaboliten X.
Questions
Compound 2 and 3 are derivatives of compound 1. Will 2
and 3 have comparable pharmacological effect to 1?
Questions
Explain how the compound can be modified in order
to obtain an improved SSRI