Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy

Abstract

This letter describes the further optimization of a series of mGlu₃ 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 (Ca²⁺ flux via a promiscuous G protein (G_α15) versus native coupling to GIRK channels), identified both full and partial mGlu₃ NAMs and a new in vivo tool compound, VU6017587. This mGlu₃ NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu₃ affords anxiolytic-like and antidepressant-like phenotypes in mice.