Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 4: SAR reveals positive cooperativity across multiple mGlu receptor subtypes leading to subtype unselective PAMs

Dexter C Davis; Joseph D Bungard; Sichen Chang; Alice L Rodriguez; Annie L Blobaum; Olivier Boutaud; Bruce J Melancon; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2020.127724

Lead optimization of the VU0486321 series of mGlu₁ PAMs. Part 4: SAR reveals positive cooperativity across multiple mGlu receptor subtypes leading to subtype unselective PAMs

Bioorg Med Chem Lett. 2021 Jan 15:32:127724. doi: 10.1016/j.bmcl.2020.127724. Epub 2020 Nov 27.

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
² Warren 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.
³ Warren 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: craig.lindsley@vanderbilt.edu.

PMID: 33253881
DOI: 10.1016/j.bmcl.2020.127724

Abstract

Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu₁ PAMs identified unique 'molecular switches' on the central aromatic ring that engendered positive cooperativity with multiple mGlu subtypes across the receptor family, resulting in compounds with comparable activity at Group I (mGlu_1/5) and Group III (mGlu_4/6/7/8) mGlu receptors, receptors. These exciting data suggests this PAM chemotype appears to bind to multiple mGlu receptors, and that subtype selectivity is dictated by the degree of cooperativity, not a subtype selective, unique allosteric binding site. Moreover, there is interesting therapeutic potential for mGlu_1/4/7/8 PAMs, as well as the first report of a GPCR allosteric 'privileged structure'.

Keywords: Metabotropic glutamate receptor; Positive allosteric modulator (PAM); Structure-activity-relationship (SAR); mGlu.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Allosteric Regulation
Coumarins / chemistry*
Coumarins / metabolism
Furans / chemistry*
Furans / metabolism
Humans
Receptor, Metabotropic Glutamate 5 / chemistry
Receptor, Metabotropic Glutamate 5 / metabolism*
Receptors, Metabotropic Glutamate / chemistry
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship

Substances

Coumarins
Furans
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate
VU0486321
metabotropic glutamate receptor type 1