Biomedical Engineering Reference
In-Depth Information
A major problem with the tricyclic antidepressants such as imipramine (
18.23
), desipramine
(
18.24
), amitriptyline (
18.26
), nortriptyline (
18.27
), and melitracen (
18.28
) is that, due to their
fundamental tricyclic structures, in addition to their blockade of SERT and/or NET, they also block
a number of postsynaptic receptors notably for acetylcholine, histamine, and NE. Therefore, they
may induce a number of anticholinergic, antihistaminergic, and cardiovascular side effects, such as
dryness of the mouth, constipation, confusion, dizziness, sedation, orthostatic hypotension, tachy-
cardia, and/or arrhythmia. Moreover, they are potentially lethal in overdose. So even if these drugs
represented a major therapeutic breakthrough, it became clear that there was an inevitable need for
better and safer drugs.
18.3.1.2 The Selective Serotonin Reuptake Inhibitors
Nortriptyline (
18.27
) is a relative selective NE reuptake inhibitor, while the corresponding dimethyl
derivative, amitriptyline (
18.26
), is a mixed 5-HT/NE reuptake inhibitor with concomitant high
afi nity for the postsynaptic receptors mentioned earlier. The same is true for the corresponding pair
desipramine (
18.24
)/imipramine (
18.23
). Swiss psychiatrist Paul Kielholz coupled these observa-
tions to the clinical proi les of these drugs, and Swedish scientist Arvid Carlsson noticed that the
tertiary amine drugs, which were mixed 5-HT and NE reuptake inhibitors, were “mood elevating,”
while the secondary amines, being primarily NE reuptake inhibitors, increased more “drive” in
the depressed patients. As the foremost quality of an antidepressant drug should be mood elevation
(elevation of drive before mood could induce a suicidal event), Carlsson advocated for the develop-
ment of selective 5-HT reuptake inhibitors. Consequently, a number of pharmaceutical companies
initiated drug discovery programs aiming at design of such drugs in the early 1970s.
18.3.1.2.1 Discovery of Cit alopram
In the mid-1960s, chemists at Lundbeck were looking for more potent derivatives of the tricyclic
compounds amitriptyline, nortriptyline, and melitracen, which the company had developed and mar-
keted previously. The tril uoromethyl group had in other in-house projects proved to increase potency
in thioxanthene derivatives with antipsychotic activity (see Figure 18.1), and it was therefore decided
to attempt to synthesize the 2-CF
3
derivative (
18.30
) of melitracen (Figure 18.5). The precursor
molecule
18.29
was readily synthesized, but attempts to ring-close it in a manner corresponding to
the existing melitracen method, using concentrated sulfuric acid, failed. However, another product
was formed, which through meticulous structural elucidation proved to be the bicyclic phthalane (or
dihydroisobenzofuran) derivative
18.31
. Fortunately, this compound was examined in models for
antidepressant activity and was very surprisingly found to be a selective NET inhibitor. Some deriva-
tives were synthesized, among them two compounds that later got the International Nonproprietary
Name (INN) names talopram (
18.32
) and talsupram (
18.33
). These compounds are still among the
most selective NE reuptake inhibitors (SNIs) ever synthesized (Figure 18.5 and Table 18.2).
Both talopram and talsupram were investigated for antidepressant effect in clinical trials but
were stopped in Phase II for various reasons, among which an activating proi le in accordance with
their potent NE reuptake inhibition. A project was therefore started in the beginning of 1971 with
the aim of discovering an SSRI from the talopram structure.
It may not be obvious to use an SNI as template structure for an SSRI. However, in the i rst series
synthesized, two compounds (
18.35
and
18.36
, Table 18.2) without the dimethylation of the phthalane
ring showed a tendency for increased 5-HT reuptake, and in accordance with the structure-activity rela-
tionship (SAR) studies mentioned earlier for tricyclics, the
N,N
-dimethyl derivative
18.36
was the more
potent. Therefore, compound
18.36
became a template structure for further structural investigation.
In this phase of the project, test models for measuring neuronal reuptake were not available, so
5-HT reuptake inhibition was measured as inhibition of tritiated 5-HT into rabbit blood platelets,
while inhibition of NE reuptake was measured
ex vivo
as inhibition of tritiated NE into the heart of
the mouse (Table 18.2). Although these models were not directly comparable, they were acceptable
for the discovery of selective compounds.
