Mapping the D2/D3 Dopamine Receptor Binding Sites

Project Details

Description

DESCRIPTION (Provided by applicant):
A variety of neurological and neuropsychiatric disorders appear to be due to
disturbance of the dopaminergic system. Since recent studies indicate that
Di-like and D4 dopamine receptor selective antagonists are not effective
antipsychotics, there is a renewed focus on D3 dopamine receptors as a target
for antipsychotic drugs used in the treatment of schizophrenia. In addition,
recent studies suggest that the D3 dopamine receptor subtype might be an
important target for the development of agents for pharmacotherapeutics that
could be used in the rehabilitation of individuals who abuse cocaine. However,
it has been difficult to develop selective D3 receptor compounds that can be
used for experimental or clinical studies on the role of the D3 dopamine
receptor subtype in neuropsychiatric disorders or drug abuse because the D2 and
D3 dopamine receptors have a high degree of amino acid sequence homology within
the transmembrane spanning regions, which construct the neutotransmitter
binding site. In collaborative studies, our laboratory has identified a series
of structurally related compounds that range from 5- to 50-fold selective for
the LB compared to the D2 dopamine receptor subtype. The experiments described
in this proposal are designed to identify the amino acid residues within the D2
and LB dopamine receptor binding sites that directly interact with the
currently available LB selective compounds. This will be accomplished by
preparing mutant receptors structurally related to the D2 and LB dopamine
receptor subtypes to precisely define the position of the pharmacophore within
the neurotranamitter binding site. The results of these studies will 1) provide
information on how our current LB dopamine receptor selective compounds bind to
the neumtransmitter binding sate and 2) provide additional structural
information that will assist us in the design of novel compounds with increased
selectivity for LB dopamine receptors
StatusFinished
Effective start/end date20/07/0131/05/02