This proposal is a collaboration between a molecular pharmacologist and a synthethic chemist to develop new compounds and to test the molecular mechanisms of allosteric enhancers (AE) of adenosine receptor function. Allosteric enhancers are a new category of drugs which work on G protein coupled receptors (and other systems) to bind to a site distinct from that of the natural agonist and enhance the activation of the receptor. This category of drugs may provide significant benefits in therapeutic specificity because these sites may not be conserved to the same degree as the orthosteric sites which bind the natural activator ligand of the receptor. The four aims of the work are to: 1) synthesize new candidate AE structures which may have improved affinity or specificity at adenosine receptor subtypes, 2) use mutagenesis and molecular modeling to identify the structural basis of AE function, 3) to biochemically evaluate receptor-G protein interactions to determine mechanisms of action of AE's and 4) to evaluate AE action in tissue models (e.g. brain ischemia) where adenosine is thought to play a role in pathophysiology.
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