Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu 3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy.

This letter describes the further optimization of a series of mGlu ₃ NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca ²⁺ flux via a promiscuous G protein (G _α15 ) versus native coupling to GIRK channels), identified both full and partial mGlu ₃ NAMs and a new in vivo tool compound, VU6017587. This mGlu ₃ NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu ₃ affords anxiolytic-like and antidepressant-like phenotypes in mice.
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