A large number of anatomical, cellular, molecular, and behavioral studies have led to the hypothesis that selective activators of mGluRS may have exciting potential as novel antipsychotic and cognition-enhancing agents. While these studies represent a major advance in our understanding of mGluRS function, selective agonists of mGluRS have not been available to directly test this hypothesis in vivo. Unfortunately, it has been difficult to develop compounds that act as selective agonists of specific mGluR subtypes that have properties that are suitable for in vivo studies or ultimate development of therapeutic agents. Over the past year, we made a major breakthrough in developing a novel approach to activation of mGluRS using selective allosteric potentiators of this receptor. These compounds do not activate mGluR5 directly but dramatically potentiate the response of the receptor to glutamate. These allosteric potentiators offer high selectivity for mGluRS and provide an exciting new approach to development of novel selective activators of G protein-coupled receptor (GPCR) subtypes. One of these compounds, termed CDPPB, is systemically active, has a relatively long half life and readily crosses the blood brain barrier. This provides an unprecedented opportunity to determine the electrophysiological and behavioral effects of selective mGluRS potentiators. Furthermore, defining the precise domains of the receptors required for this action and the mechanisms involved in allosteric potentiation of mGluRs by CDPPB and its analogs will be important for further development of this approach to mGluR activation. We now propose a series of molecular, structure function, and pharmacological studies to rigorously test the hypothesis that potentiation of mGluRS responses by CDPPB and its analogs is mediated by binding to an allosteric binding site on mGluRS that also binds to allosteric antagonists of this receptor, such as MPEP. In addition, we will determine the electrophysiological effects of CDPPB on activation of mGluRS by exogenous agonists and stimulation of glutamatergic afferents in systems that may be important for potential antipsychotic and cognition-enhancing effects of this compound. Finally, we will determine the behavioral effects of CDPPB in animal models that have been used to assess potential antipsychotic and cognition-enhancing activity of novel agents. These studies will have a major impact on our understanding of mGluRS function and an exciting new approach to activation of this receptor with allosteric potentiators. In addition, these studies will have a major impact on thinking about the utility of allosteric potentiators for multiple other GPCRs where development of direct agonists has been problematic. ? ?
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