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

Previous
preclinical work has demonstrated the therapeutic potential
of antagonists of the group II metabotropic glutamate receptors (mGlus).
Still, compounds that are selective for the individual group II mGlus
(mGlu2 and mGlu3) have been scarce. There remains
a need for such compounds with the balance of properties suitable
for convenient use in a wide array of rodent behavioral studies. We
describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo­[1,5-a]­pyrazine-4­(5H)-one compounds originally
identified as a mGlu5 positive allosteric modulator (PAM)
chemotype. Its suitability for use in rodent behavioral models has
been established by extensive in vivo PK studies, and the behavioral
experiments presented here with compound 106 represent
the first examples in which an mGlu3 NAM has demonstrated
efficacy in models where prior efficacy had previously been noted
with nonselective group II antagonists.