Allosteric modulators of GPCRs as a novel approach to treatment of CNS disorders
Jeffrey Conn,
Director,
Vanderbilt University School of Medicine
Scientists in academic settings have made tremendous advances in understanding human disease but often fail to make critical links that allow this information to be useful in industry settings. Likewise, fiscal pressures make it increasingly difficult for companies to invest in basic research needed to translate these discoveries into marketable products. The Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) invests in early stage drug discovery with a goal of de-risking investment in innovative approaches to treatment of serious brain disorders in industry settings. VCNDD scientists work in a focused team fashion to advance novel target validation, lead discovery, and lead optimization for generation of quality clinical candidates. These drug discovery efforts are fully integrated with an intense focus on the highest level of academic basic research to allow optimization of drug candidates that represent highly innovative new approaches to treatment of CNS disorders. The VCNDD has pioneered discovery and development of highly selective allosteric modulators of multiple GPCR subtypes that are now advancing in development for treatment of a range of CNS disorders. For instance, we have identified the metabotropic glutamate receptor, mGluR4, as an exciting new target for treatment of Parkinson’s disease. Unfortunately, it has been difficult to develop compounds that act as selective orthosteric agonists of mGluR4 or other mGluR subtypes that have properties that are likely to be suitable for development of therapeutic agents. We discovered and chemically optimized selective positive allosteric modulators (PAMs) for mGluR4. These compounds do not activate mGluR4 directly but dramatically potentiate the response of these receptors to glutamate. These allosteric potentiators offer high selectivity for mGluR4 and provide an exciting new approach to development of novel selective activators of this and other GPCR subtypes. Highly selective mGluR4 PAMs ha
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