Biomedical Engineering Reference
In-Depth Information
The SSRIs have been highly successful in the treatment of depression due to their high safety in
use, and a number of new indications (e.g., panic disorder, obsessive compulsive disorder, and social
phobia) have been registered for many of these drugs in addition to major depression. However, there
are still major unmet needs in the treatment of depression, and since the inhibition of 5-HT reuptake
ensures a certain degree of antidepressant activity, there has been a large interest in combining
5-HT reuptake inhibition with additional pharmacological effects. Some of these have resulted in
marketed antidepressants, such as the SNRIs. In the following text, key events related to the discov-
ery of antidepressants and in particular citalopram and escitalopram at Lundbeck will be discussed,
including the use of pharmacophore and homology models.
18.3.1.1 First Generation Drugs
The pharmacotherapy of depression started in the late 1950s with the introduction of the two
drugs iproniazid (
18.21
) and imipramine (
18.23
, Figure 18.4). Iproniazid was originally an antitu-
berculosis drug, but it was noticed that the drug had an antidepressant effect. It was subsequently
discovered that iproniazid was an unselective, irreversible inhibitor of the enzymes MAO-A and
MAO-B, which deaminate the monoamines NE, DA, and 5-HT. Structural modii cations of the
tricyclic antipsychotic drugs with chlorpromazine (
18.1
, Figure 18.1) as a prototype led to the
6-7-6 tricyclic compound imipramine that was found to block the transporters for NE and 5-HT.
These mechanisms led to an increase in the concentrations of NE and 5-HT in the synapse, which
in turn led to the so-called amine hypothesis of depression, stating that there is a decreased avail-
ability of these neurotransmitters in depression.
Although the discovery of these two classes of drugs was of major therapeutic importance, it
quickly turned out that both types had fatal side effects. Treatment with MAO inhibitors could
induce a hypertensive crisis because of a fatal interaction with foodstuffs containing tyramine
such as cheese. Dietary restrictions during treatment with MAO inhibitors were therefore required.
Reversible MAO-A inhibitors (such as moclobemide (
18.22
)) have later been developed, but such
drugs are still not completely devoid of the “cheese-effect” because the tyramine potentiation is
inherent to blockade of MAO-A in the periphery. MAO inhibitors are therefore only used to a lesser
extent in antidepressant therapy.
O
O
N
Cl
HN
NH
HN
NO
Iproniazid (
18.21
)
Moclobemide (
18.22
)
R´
CH
3
R
CH
3
CH
3
CH
3
N
N
N
R
N
Imipramine (R´ = H; R = CH
3
) (
18.23
)
Desipramine (R´ = H; R = H) (
18.24
)
Clomipramine (R´ = Cl; R = CH
3
) (
18.25
)
Amitriptyline (R = CH
3
) (
18.26
)
Nortriptyline (R = H) (
18.27
)
Melitracen (
18.28
)
FIGURE 18.4
Antidepressant drugs from MAO-inhibitor and tricyclic classes.
