Biomedical Engineering Reference
In-Depth Information
18.2.1.2 Atypical Antipsychotic Drugs
Isoclozapine (
18.8
, Figure 18.1), which has the “neuroleptic chloro substituent” in benzene ring
A
,
is a classical antipsychotic drug. On the contrary, clozapine (
18.10
, Figure 18.2), which has the
chloro substituent in benzene ring
C
(Figure 18.1), has revolutionized the pharmacotherapy of
schizophrenia. Thus, clozapine was the i rst antipsychotic drug that was effective in the treatment
of positive symptoms of schizophrenia and free of EPS, but unfortunately clozapine can cause fatal
agranulocytosis in a small percentage (1%-2%) of individuals, and much effort has been directed
toward the identii cation of new antipsychotics with a clozapine-like clinical proi le but without the
risk of causing agranulocytosis.
This search has resulted in a number of atypical antipsychotics such as olanzapine (
18.11
), que-
tiapine (
18.12
), risperidone (
18.13
), ziprasidone (
18.14
), aripiprazole (
18.15
), and sertindole (
18.16
)
(Figure 18.2). The structure of these compounds reveals that olanzapine and quetiapine were
obtained by structural modii cation of clozapine, whereas risperidone and ziprasidone were obtained
from the butyrophenones. Aripiprazole and sertindole are quite different in chemical structure, and
the discovery of sertindole will be discussed in more detail in the following text.
In vitro
binding data for selected DA, 5-HT, and NE receptors as well as data from the catalepsy
model (
in vivo
rat model predictive of EPS in humans) are shown for haloperidol and key atypical
antipsychotics (Table 18.1). All the compounds display mixed receptor proi les with afi nity for even
more receptors and sites than included in the table (data not shown). The tendency is that classical
antipsychotics display high afi nity for D
2
receptors relative to 5-HT
2A
receptors, whereas the atypi-
cal antipsychotics display an increased afi nity for 5-HT
2A
receptors relative to D
2
. The relative ratio
of D
2
versus 5-HT
2A
receptor afi nity has been suggested as a reason for atypicals not giving rise to
EPS at therapeutic doses. A number of other factors may inl uence both the antipsychotic potential
and the propensity to induce EPS, such as the afi nity and efi cacy at some of the other receptors,
but also
in vivo
preference for limbic versus striatal regions of the brain might explain these differ-
ences. Interestingly, aripiprazole is a partial D
2
receptor agonist, whereas the other antipsychotics
are D
2
receptor antagonist. Partial D
2
receptor agonists are envisaged to stabilize a dysfunctioning
N
N
S
S
H
3
C
Cl
N
N
N
N
N
N
N
N
N
HO
H
3
C
H
3
C
O
Clozapine (
18.10
)
Olanzapine (
18.11
)
Quetiapine (
18.12
)
F
Cl
Cl
Cl
F
S
O
N
N
N
N
N
N
N
N
N
O
O
O
Cl
N
N
NH
HN
H
N
O
O
Risperidone (
18.13
)
Ziprasidone (
18.14
)
Aripiprazole (
18.15
)
Sertindole (
18.16
)
FIGURE 18.2
Atypical antipsychotic drugs.
