Projects

Current Projects | Archived Projects
There are 5 current projects in the NDRC.

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A Novel Molecular Site for Antidopaminergic Action

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Principal Investigator(s)
Richard Mailman

Funding Agency
NIMH

Project Duration
04/01/1985 to 01/31/2010

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A major aim is to map functionally important sites of D1 like receptors. Structural data will be developed by creating selected site-directed D1 and D5 mutant receptors, and using structurally rigid drugs as critical probes. The ability of these probes to bind and/or activate adenylate cyclase via the mutant receptors, will be tested. These probes are derived from rigid full agonists we have developed previously, but contain structural modifications that will test various aspects of the docking models of our well-tested pharmacophore. A second aim is receptor and ligand modeling of the D1 receptor. This aim builds on our foundation of interactive ligand-based modeling, chemical synthesis, and molecular pharmacology, with the goal to elucidate key structural features that determine ligand binding to the D1 receptor, and later, more subtle factors that affect ligand intrinsic efficacy with a given receptor. The goal of these studies is to understand the 3D structure of the receptor, especially its active site, and to use this information to understand how ligands bind to the receptor and affect its function. This is complemented by several strategies of ligand-based molecular modeling to refine existing models, and test the hypothesis of alternate binding models for D1 and D5 receptors. Finally, we are designing and testing novel D1-like ligands with one goal being the development of selective D1 and D5 ligands.