Project Summary

P. Jeffrey Conn, Ph.D. (Distinguished Investigator 2004) of Vanderbilt University, will study the possibility that a subtype of metabotropic glutamate receptor (mGluR) may be a closely associated signaling partner with the NMDA receptor (NMDAR) and may play an integral role regulating and setting the tone of NMDAR function. It is believed that compounds that promote the function of NMDARs may ameliorate the symptoms of schizophrenia. Dr. Conn believes that it is possible that agonists of mGluR5 or agents that facilitate mGluR5 function could provide novel therapeutic agents that may be useful for treatment of schizophrenia, and based on prior data, further suggests that mGluR5 receptors play a modulatory role on rodent behaviors known to be sensitive to NMDAR antagonist modulation and add further support to the possibility that activators of mGluR5 may provide a novel approach that could be useful in the treatment of schizophrenia. However, it has been difficult to develop agonists that selectively activate mGluR5 and have properties that are desirable in drug-like molecules. Dr. Conn recently discovered a series of small molecules that do not activate mGluR5 directly but act at an allosteric site on the receptor to promote glutamate-induced activation of the receptor. He proposes a series of studies in which he will screen a small molecule library for novel mGluR5 potentiators that have more favorable properties for further studies of potential antipsychotic efficacy. He will also test whether allosteric potentiators of mGluR5 potentiate effects of this receptor on NMDAR currents and have an antipsychotic-like profile in animal models. Dr. Conn hopes this study will provide lead molecules that could be used for future drug discovery efforts by pharmaceutical companies.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

Search Again