Differential Pharmacology and Binding of mGlu Receptor Allosteric Modulators.

O'Brien DE, Shaw DM, Cho HP, Cross AJ, Wesolowski SS, Felts AS, Bergare J, Elmore CS, Lindsley CW, Niswender CM, Conn PJ
Mol Pharmacol. 2018 93 (5): 526-540

PMID: 29545267 · PMCID: PMC5894801 · DOI:10.1124/mol.117.110114

Allosteric modulation of metabotropic glutamate receptor 2 (mGlu) has demonstrated efficacy in preclinical rodent models of several brain disorders, leading to industry and academic drug discovery efforts. Although the pharmacology and binding sites of some mGlu allosteric modulators have been characterized previously, questions remain about the nature of the allosteric mechanism of cooperativity with glutamate and whether structurally diverse allosteric modulators bind in an identical manner to specific allosteric sites. To further investigate the in vitro pharmacology of mGlu allosteric modulators, we developed and characterized a novel mGlu positive allosteric modulator (PAM) radioligand in parallel with functional studies of a structurally diverse set of mGlu PAMs and negative allosteric modulators (NAMs). Using an operational model of allosterism to analyze the functional data, we found that PAMs affect both the affinity and efficacy of glutamate at mGlu, whereas NAMs predominantly affect the efficacy of glutamate in our assay system. More importantly, we found that binding of a novel mGlu PAM radioligand was inhibited by multiple structurally diverse PAMs and NAMs, indicating that they may bind to the mGlu allosteric site labeled with the novel mGlu PAM radioligand; however, further studies suggested that these allosteric modulators do not all interact with the radioligand in an identical manner. Together, these findings provide new insights into the binding sites and modes of efficacy of different structurally and functionally distinct mGlu allosteric modulators and suggest that different ligands either interact with distinct sites or adapt different binding poses to shared allosteric site(s).

Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

MeSH Terms (13)

Allosteric Regulation Allosteric Site Animals Cell Line Glutamic Acid HEK293 Cells Humans Ligands Mutagenesis Protein Binding Radioligand Assay Rats Receptors, Metabotropic Glutamate

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