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

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

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)

Tricyclic antidepressants

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.

Tricyclic antidepressants

1. Based on the middle ring, or ring B

Dibenzazepines: have a nitrogen at C5 (Imipramine, trimepramine,

clomipramine, desipramine)

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?

Tricyclic antidepressants

Metabolism of clomipramine

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 5-

HT2 and 5-HT3 receptors—thereby enhance serotonergic

neurotransmission while causing a low incidence of side effects

Tricyclic antidepressants

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

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)

Selective serotonin reuptake

inhibitors (SSRIs)

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

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

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

N,N disubstitution on one end decreases, or loses, potency

Phenelzine

MAOI antidepresants

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

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

MAOI antidepresants

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)

MAOI antidepresants

► 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)

CHC

CH3

CH3

N

CH3

NH

CH3

NH2

MAOI antidepresants

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.

The first approved antidepressant to incorporate a non-monoaminergic

mechanism of action.

Agomelatine

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