Biomedical Engineering Reference
In-Depth Information
Thioxanthenes
Phenothiazines
S
S
R
N
R
N
N
N
N
S
HO
HO
Cl
N
Perphenazine (R = Cl) (
18.2
)
Fluphenazine (R = CF
3
) (
18.3
)
Zuclopenthixol (R = Cl) (
18.4
)
(Z)-Flupentixol (R = CF
3
) (
18.5
)
H
3
C
N
CH
3
6-7-6 tricyclics
Butyrophenones
F
X
Chlorpromazine (
18.1
)
A
C
O
B
R
Y
N
N
N
HO
H
3
C
Loxapine (R = Cl, X = O, Y = N, unsaturated bond) (
18.6
)
Octoclothepin (R = Cl, X = S, Y = CH
2
, saturated bond) (
18.7
)
Isoclozapine (R = Cl, X = NH, Y = N, unsaturated bond) (
18.8
)
Haloperidol (
18.9
)
Cl
FIGURE 18.1
Classical antipsychotic drugs.
Denmark investigated in particular the thioxanthene backbone, and this work resulted in drugs such
as zuclopenthixol (
18.4
) and (Z)-l upentixol (
18.5
) (Figure 18.1). The 6-7-6 tricyclic backbone has
also led to a number of classical antipsychotic drugs such as loxapine (
18.6
), octoclothepin (
18.7
),
and isoclozapine (
18.8
) (Figure 18.1). The R group found in all of these compounds is called the
“neuroleptic substituent,” and this substituent increases the D
2
afi nity/antagonism relative to unsub-
stituted molecules and is essential for potent neuroleptic effect.
In the late 1950s, researchers at Janssen discovered an entirely new class of classical antipsychotic
drugs without a tricyclic structure, namely the butyrophenones. Haloperidol (
18.9
, Figure 18.1) is the
most prominent representative of this class of compounds, and today haloperidol is considered
the archetypical classical antipsychotic drug for both preclinical experiments and clinical trials.
The classical antipsychotic drugs were all discovered using
in vivo
animal models, as the cur-
rent knowledge about receptor multiplicity and
in vitro
receptor-binding techniques were unknown
at that time. However, many of the
in vivo
models, which were used at that time as predictive for
antipsychotic effect, is today considered more predictive of various side effects, e.g., EPS, and in
hindsight it was difi cult to i nd new antipsychotic drugs without the potential to induce EPS with
the models available at that time. Thus, the development of new animal models modeling key prop-
erties of putative new antipsychotics is essential to the progress toward novel pharmacotherapies
of schizophrenia. The ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC)
model is a good example of such a “model breakthrough” (see the following text).
An examination of the classical antipsychotic drugs by today's range of receptor-binding tech-
niques and other more advanced biochemical methods has revealed that these drugs are postsynaptic
D
2
receptor antagonists, and it is believed that this accounts for both their antipsychotic effect as well
as their potential to induce EPS. However, these drugs also target several other receptors, which may
contribute to both their antipsychotic effect, and to their side effect proi le.
