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

摘要

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%.