Biomedical Engineering Reference
In-Depth Information
this x-ray structure has given a new insight into the structure of mammalian transporters, and a
SERT homology model will be discussed as an example of the application of computational meth-
ods in drug design (Section 18.3.1.4). The structure and function of transporters are discussed in
more detail in Chapter 14.
Selective ligands have been described for many of these receptor subtypes and transporters
and in the following text, we have chosen to focus on ligands that have shown potential as antip-
sychotic or antidepressant drugs or which have been important in the discovery of these ligands.
Antipsychotic drugs that are used in the treatment of schizophrenia will be discussed as an example
of ligands for DA and 5-HT receptors (Section 18.2), whereas antidepressant drugs that are used for
the treatment of depression and anxiety will be discussed as examples of ligands for transporters
(Section 18.3).
18.2 RECEPTOR LIGANDS
18.2.1 A
NTIPSYCHOTIC
D
RUGS
Antipsychotic drugs are primarily used to treat schizophrenia. Schizophrenia is distinguished from
other psychotic disorders based on a characteristic cluster of symptoms, where the positive symp-
toms appear to rel ect an excess or distortion of normal function (i.e., delusion, hallucinations, disor-
ganized thinking, disorganized behavior, and catatonia), whereas the negative symptoms appear to
rel ect a diminution or loss of normal functions (i.e., affective l attening, poverty of speech, and an
inability to initiate and persist in goal-directed activities). The cognitive symptoms (i.e., impairment
of memory, executive function, and attention) have in recent years attracted more and more atten-
tion, and recently much research is directed toward understanding the role of these symptoms.
The antipsychotic drugs are divided into the classical and the atypical antipsychotic drugs. The
classical antipsychotic drugs were discovered in the 1950s with chlorpromazine (
18.1
, Figure 18.1)
as the i rst prominent example, whereas the atypical antipsychotic drugs were introduced into the
treatment of schizophrenia during the 1990s. It is believed that the antipsychotic drugs exert their
effect on positive symptoms by reducing DA hyperactivity in limbic areas of the brain.
The term classical antipsychotic drug is linked to compounds that show effect in the treatment of
positive symptoms at similar doses that induce extrapyramidal symptoms (EPS, i.e., Parkinsonian
symptoms, dystonia, akathisia, and tardive dyskinesia). It is believed that EPS is caused by the
blockade of DA activity in striatal areas of the brain. The classical antipsychotic drugs are without
effect on negative and cognitive symptoms, and these drugs may even worsen these symptoms. It
has been argued that the deterioration of negative and cognitive symptoms by classical antipsychotic
drugs may be a consequence of their EPS, and the separation of the antipsychotic effect and EPS is
the foremost important property of the atypical antipsychotic drugs.
Thus, the term atypical antipsychotic drug is linked to a diverse group of drugs having antip-
sychotic effect at doses not giving EPS. However, all drugs from this group have their own com-
pound specii c limitations, such as a strong tendency to increase weight for some of the compounds,
whereas others have a tendency to prolong the QT interval (total duration of cardiac ventricular
electrical activity) in the surface electrocardiogram. In the following text, the classical as well as
atypical antipsychotic drugs will be discussed with focus on their discovery, including structural
considerations and pharmacological proi le of key compounds.
18.2.1.1 Classical Antipsychotic Drugs
Chlorpromazine was discovered in the beginning of the 1950s, and the structure of chlorpromazine
with its phenothiazine backbone was an excellent lead for medicinal chemists. Thus, the modii cation
of chlorpromazine without changing the phenothiazine backbone led to a number of drugs such as
perphenazine (
18.2
) and l uphenazine (
18.3
) (Figure 18.1). Medicinal chemists also replaced the
phenothiazine backbone with other tricyclic structures, and these modii cations led to other classes
of classical antipsychotic drugs such as the thioxanthenes and the 6-7-6 tricyclics. Lundbeck in
