Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds

Yousuke Yamada; Kristen Gilliland; Zixiu Xiang; Daniel Haymer; Katherine E Crocker; Matthew T Loch; Michael L Schulte; Alice L Rodriguez; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Bruce J Melancon

doi:10.1016/j.bmcl.2021.128342

Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds

Bioorg Med Chem Lett. 2021 Oct 15:50:128342. doi: 10.1016/j.bmcl.2021.128342. Epub 2021 Aug 27.

Affiliations

¹ Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA.
² Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
³ Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, 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 School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁴ Warren Center for Neuroscience Drug Discovery at Vanderbilt University, 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; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: bruce.melancon@vanderbilt.edu.

PMID: 34461178
DOI: 10.1016/j.bmcl.2021.128342

Abstract

This letter describes synthesis and evaluation of two series of dual mGlu₂/mGlu₃ positive allosteric modulators with moderate mGlu₃ potency and robust mGlu₂ potency in thallium flux assays. These compounds were profiled their ability to modulate mGlu₃-mediated signaling in central neurons by co-application of a selective mGlu₂ NAM to isolate mGlu₃-selective effects. Using acute mouse brain slices from the prefrontal cortex, potentiation of group II mGlu receptor agonist Ca²⁺ signaling in PFC pyramidal cells with either the dual mGlu₂/mGlu₃ PAM 16e or 23d demonstrated effects mediated selectively via mGlu₃.

Keywords: Glutamate; Metabotropic; Positive allosteric modulator (PAM); Structure activity relationship (SAR); mGluR(3).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium Signaling / drug effects*
Cell Line
Drug Design
Humans
Mice
Molecular Structure
Neurons / drug effects
Neurons / metabolism*
Prefrontal Cortex / cytology
Pyramidal Cells
Receptors, Metabotropic Glutamate / administration & dosage*
Receptors, Metabotropic Glutamate / agonists*
Receptors, Metabotropic Glutamate / genetics
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship

Substances

Receptors, Metabotropic Glutamate
metabotropic glutamate receptor 2
metabotropic glutamate receptor 3