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

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

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2670-2674. doi: 10.1016/j.bmcl.2019.07.030.
Yosuke Yamada 1,  Samantha E Yohn 2,  Kristen Gilliland 1,  Mathew T Loch 1,  Michael L Schulte 2,  Alice L Rodriguez 2,  Anna L Blobaum 2,  Colleen M Niswender 3,  P Jeffrey Conn 3,  Craig W Lindsley 4
Affiliations

Affiliations

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
  • 3 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
  • 4 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
PMID: 31358468 DOI: 10.1016/j.bmcl.2019.07.030
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 (Gα15) 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.

Keywords

Metabotropic glutamate receptor; Negative allosteric modulator (NAM); Structure-Activity Relationship (SAR); mGlu(3).

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