VU0469650 is a brain-penetrant, potent and selective metabotropic glutamate receptor 1 (mGlu1) negative allosteric modulator (NAM). VU0469650 selectively inhibits glu-induced Ca2+ influx in human mGluR1-expressing HEK 293A (EC50 = 99 nM with [Glu] = EC20 for 1.9 min, then EC100 for 1.7 min; inactive against cells expressing human mGlu2-8 at 10 μM) with no affinity toward a panel of 68 clinically relevant GPCRs, ion channels, kinases, and transporters. Prior administration of VU0469650 in mice in vivo (60 mg/kg i.p.) modulates the antipsychotic activity of M4 muscarinic receptor PAM VU0467154 and th at of the M1/M4 agonist xanomeline.
