One thing that complicates the development
of drugs, means Håkan, is that it is possible to get different
results with one and the same substance depending on whether the
studies are performed in test tubes (in vitro) or in living people
(in vivo). In the body, there are enzymes that can degrade and thereby
alter the properties of the molecules in a way that changes the
effects they exert. The same enzymes also complicate the evaluation
of dose-response curves for medications. It is hard do anticipate
how much of the administered drug that will be degraded by these
enzymes before it has reaches its goal and exerts an effect.
Håkan experienced this phenomenon when
he together with his colleague at Astra, Sven-Ove Ögren, was
working with developing a new antipsychotic  drug
in the late eighties. While Håkan was performing his studies
in vitro on tissue preparations taken from the rat brain, Sven-Ove
Ögren performed his experiments in vivo in living rats. Despite
the fact that they both used the same substance, Håkan had
to use much higher concentrations in order to see a response to
the substance. Subsequent analyses of the substance showed that
when it was administered in vivo, it was degraded into two different
metabolites, which were much more potent than the mother substance.
Hence, it was the effects of these metabolites that Ögren had
observed. Several analogs to these metabolites were then developed
to serve as radioligands for analysis of very low concentrations
of receptors. Of these, epidepride can be mentioned as a highly
active radiologand.
In schizophrenic research, the so-called
basal ganglia (i.e. caudatus and putamen) are the most extensively
studied areas of the brain. These contain receptors for dopamine
as well as serotonin, both of which have been shown to be of importance
in schizophrenia, and therefore are targets for many of the antipsychotic
drugs on the market. Thanks to epidepride, extrastriatal dopamine
receptors can today be studied in areas like the thalamus and the
cortex. These areas, which have very low levels of receptors, have
more and more, together with dopamine, come to be in focus when
studying schizophrenia.
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