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

Yamada Y, Yohn SE, Gilliland K, Loch MT, Schulte ML, Rodriguez AL, Blobaum AL, Niswender CM, Jeffrey Conn P, Lindsley CW
Bioorg Med Chem Lett. 2019 29 (18): 2670-2674

PMID: 31358468 · DOI:10.1016/j.bmcl.2019.07.030

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

Copyright © 2019 Elsevier Ltd. All rights reserved.

MeSH Terms (11)

Animals Anti-Anxiety Agents Antidepressive Agents Dose-Response Relationship, Drug Mice Molecular Structure Pyridones Rats Receptors, Metabotropic Glutamate Stereoisomerism Structure-Activity Relationship

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