Project: Research project

Project Details


These neuropharmacological studies application will study the biochemical
and molecular mechanisms by which the D1 subclass of dopamine receptors
cause their psychopharmacological effects. Several hypotheses will be
tested: that there is biochemical heterogeneity of D1 receptors; that only
a subset of these receptors are linked biochemically to cAMP synthesis;
that a subset of these D1 dopamine receptors interact functionally with D2
receptors as part of the same multimolecular complex; and that it is
possible to model this receptor class at the molecular level and to use
such models to design drugs that have selectivity for certain
subpopulations of D1 receptors. These hypotheses will be tested by
studying the basis for apparent multiplicity of D1-like receptors, e.g., by
comparing the occurrence of [3H]-SCH23390 binding sites versus
dopamine-sensitive adenylate cyclase activity (DA-ACase) or the potency of
selected drugs to cause dopaminergically-mediated behaviors. Lesioning and
pharmacological studies will be used to compare limbic areas to striatum on
the basis of these functional and receptor characteristics. Several series
of rigid and semi-rigid dopamine agonists and antagonists will be compared
using both in vivo and in vitro pharmacological methods. These data will
be used in computer-assisted molecular modeling studies to model the active
site of D1 receptors. Although initially these studies will assume a
single receptor, it is assumed that the biological studies ultimately will
provide data permitting at least two types of sites (e.g., one linked to
stimulation of adenylate cyclase, and one not) to be modeled and defined.
The molecular modeling studies will be modified continually to incorporate
the data from receptor solubilization, purification, and characterization
studies which will be a major emphasis of this research. As a consequence
of our demonstration that SCH23390 binds tenaciously to its physiologically
important receptor(s), the purification experiments will rely heavily on
affinity chromatography using a 4-alkylphenyl-substituted analog of
SCH23390 that we will synthesize. The availability of purified or
partially purified receptor(s) will lead to raising of antibodies against
these proteins, and to the initiation of molecular biological study of
these proteins. We will perform immunohistochemical localization of these
receptors, and also conduct immunoneutralization studies. The molecular
biological studies will be aimed at the physiological mechanisms involved
in expression and regulation of D1 receptors (e.g., synthesis,
posttranslational modifications, sites of expression, etc.).
Effective start/end date4/1/853/31/92


  • National Institutes of Health

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