Development and profiling of mGlu7 NAMs with a range of saturable inhibition of agonist responses in vitro

Carson W Reed; Alice L Rodriguez; Jacob J Kalbfleisch; Mabel Seto; Matthew T Jenkins; Anna L Blobaum; Sichen Chang; Craig W Lindsley; Colleen M Niswender

doi:10.1016/j.bmcl.2022.128923

Development and profiling of mGlu₇ NAMs with a range of saturable inhibition of agonist responses in vitro

Bioorg Med Chem Lett. 2022 Oct 15:74:128923. doi: 10.1016/j.bmcl.2022.128923. Epub 2022 Aug 6.

Authors

Carson W Reed¹, Alice L Rodriguez¹, Jacob J Kalbfleisch¹, Mabel Seto¹, Matthew T Jenkins¹, Anna L Blobaum¹, Sichen Chang¹, Craig W Lindsley², Colleen M Niswender³

Affiliations

¹ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States.
² Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
³ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, United States. Electronic address: colleen.niswender@vanderbilt.edu.

Abstract

We describe here a series of metabotropic glutamate receptor 7 (mGlu₇) negative allosteric modulators (NAMs) with a saturable range of activity in inhibiting responses to an orthosteric agonist in two distinct in vitro pharmacological assays. The range of inhibition among compounds in this scaffold provides highly structurally related ligands with differential degrees of receptor blockade that can be used to understand inhibitory efficacy profiles in native tissue or in vivo.

Keywords: Metabotropic glutamate receptor; Positive Allosteric modulator (PAM); Structure Activity Relationship (SAR); mGlu(7).

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Allosteric Regulation*
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Abstract

Publication types

MeSH terms

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Grants and funding