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Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGlu2/4 heterodimeric receptor results in a compound with mGlu2/2 homodimer selectivity.

Authors
  • Fulton, Mark G1
  • Loch, Matthew T2
  • Rodriguez, Alice L2
  • Lin, Xin3
  • Javitch, Jonathan A4
  • Conn, P Jeffrey5
  • Niswender, Colleen M5
  • Lindsley, Craig W6
  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3 Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA.
  • 4 Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA; Department of Pharmacology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
  • 5 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
  • 6 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, 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; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Apr 25, 2020
Pages
127212–127212
Identifiers
DOI: 10.1016/j.bmcl.2020.127212
PMID: 32371100
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu2/4 heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu2 PAM at one terminus and an mGlu4 PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu2 and mGlu4 but also in cells expressing mGlu2 or mGlu4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu2/2 homodimer over heterodimeric mGlu2/4 or homomeric mGlu4/4. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs. Copyright © 2020 Elsevier Ltd. All rights reserved.

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