Glutamate, the major excitatory neurotransmitter in the central nervous system, signals through both ionotropic and metabotropic glutamate receptors. Of the eight metabotropic glutamate receptors (mGlus) discovered thus far, development of inhibitors to mGlu5 has been given significant attention in preclinical models of disease, including pain, anxiety, gastresophageal reflux disease, Parkinson’s associated dyskinesia, and fragile X syndrome, as well as in animal models of drug addiction. VU0360223 is a noncompetitive antagonist (negative allosteric modulator) of mGlu5 that demonstrates an IC50 value of 61 nM in a calcium mobilization assay and a Ki value of 477 nM in a radioligand binding assay. A 10 μM concentration of VU0360223 results in a near complete blockade of the glutamate response in cortical astrocytes. A 30 mg/kg dose of VU0360223 in mice yields potent inhibition in a marble burying model of anxiety and is efficacious in an operant sensation seeking model of addiction.
