Discovery of a Selective and CNS Penetrant NegativeAllosteric Modulator of Metabotropic Glutamate Receptor Subtype 3with Antidepressant and Anxiolytic Activity in Rodents.

Previouspreclinical work has demonstrated the therapeutic potentialof antagonists of the group II metabotropic glutamate receptors (mGlus).Still, compounds that are selective for the individual group II mGlus(mGlu2and mGlu3) have been scarce. There remainsa need for such compounds with the balance of properties suitablefor convenient use in a wide array of rodent behavioral studies. Wedescribe here the discovery of a selective mGlu3NAM 106(VU0650786) suitable for in vivo work. Compound 106is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originallyidentified as a mGlu5positive allosteric modulator (PAM)chemotype. Its suitability for use in rodent behavioral models hasbeen established by extensive in vivo PK studies, and the behavioralexperiments presented here with compound 106representthe first examples in which an mGlu3NAM has demonstratedefficacy in models where prior efficacy had previously been notedwith nonselective group II antagonists. [ABSTRACT FROM AUTHOR]