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Re: Investigational drug assay and specific receptors.

Posted by PeterJ on April 27, 2000, at 3:24:24

In reply to Re: Investigational drug assay and specific receptors., posted by Dr. Fried on April 27, 2000, at 0:51:02

> Are these experimental receptors known to correlate well with the target receptors in the human brain? I am wondering if the models have any bugs in them. Can human brain tissue be grown in vitro under any conditions? Would there be any point in doing this, would it be a more valid experimental model?

The correlation with brain receptors is good but not perfect. Since
the receptors are created from cloned human DNA their amino acid sequence
should be the exact sequence of the desired receptor. However,
differences in the cell membrane can affect the structure of the
receptor in subtle ways.

Drug companies do try to use systems which accurately reflect the brain,
since -- for their own self interest if nothing else -- they want to get
drugs that work. They often use one proceedure for initial screening
and then use more complex proceedures to refine their understanding
of a given drug.

Binding studies are only one stage in the process. For example a
chemical which is found to bind to a specfic receptor may then be
tested in animal tissues or whole animals to see if a specific
repsonse associated with that receptor is produced.

Human brain tissue can be grown; but the cultures I am aware of are
generally derived from some type of brain tumor (astrocytoma or
glioblastoma). Tumor cells are immortalized and grow in an unrestricted
manner. That's what makes them tumors but that also makes them easy
to grow in cell cultures.

Using real human brain cells might have some advantages, but also
some problems. Non-tumor cells are difficult to culture. Also
brain cells will express a large number of receptors which would make
it much harder if you only want to study binding to one specific

Post mortem human brain tissue is often studied in basic research on
receptors. The receptors survive and will still bind drugs after death.

It is even possible to study receptor binding in brains of living
people using PET scan techniques. This is too difficult to do in
drug screening, but has been done in studying the effects of drugs.
For example, there have been several PET studies showing differences
in binding of typical vs. atypical antipsychotics. These studies
have also been helpful in determining the optimum dosage of drugs,
for example a dose of risperidone which will block 5-HT2 receptors
without fully blocking DA receptors.





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