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

Basic Information

ID: ALA4346754

Journal: Bioorg Med Chem Lett

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

Authors: Yamada Y, Yohn SE, Gilliland K, Loch MT, Schulte ML, Rodriguez AL, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW.

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.

CiteXplore: 31358468

DOI: 10.1016/j.bmcl.2019.07.030

Patent ID: ┄

Associated Items: Associated Bioactivities Associated Assays Associated Compounds Associated Targets