Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: Unexpected ‘molecular switch’ from a closely related mGlu4 positive allosteric modulator

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Abstract

Herein we report the discovery and SAR of a novel antagonist of metabotropic glutamate receptor 4 (mGlu4). The antagonist was discovered via a molecular switch from a closely related mGlu4 positive allosteric modulator (PAM). This antagonist (VU0448383) displays an IC50 value of 8.2 ± 0.4 μM and inhibits an EC80 glutamate response by 63.1 ± 6.6%.

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Acknowledgments

The authors acknowledge C. David Weaver, Emily Days, and Christopher Farmer of the Vanderbilt High Throughput Screening facility. This work was supported by Grants from the NIH and Michael J. Fox Foundation.

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These authors equally contributed to this work.

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