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Herein, we report a potent, CNS penetrant, orally bioavailable metabotropic glutamate receptor subtype 8 (mGlu8) positive allosteric modulator (PAM), VU6081679, that shows robust efficacy in a rodent model of Parkinson's disease. A high-throughput screening effort and subsequent structure-activity relationship study led to the discovery of VU6081679, an mGlu8-preferring PAM with good potency at rat, mouse, and human mGlu8. Molecular docking into a published cryo-EM structure supports binding in an allosteric pocket at the extracellular TM6/TM7 dimer interface. VU6081679 displays a favorable rodent DMPK profile and demonstrates robust efficacy in a haloperidol-induced catalepsy model of Parkinson's disease in both rats and mice. Additional studies conducted in mGlu8 knockout mice confirmed that the observed efficacy is mGlu8-mediated.
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