@article {O{\textquoteright}Brien526, author = {Daniel E. O{\textquoteright}Brien and Douglas M. Shaw and Hyekyung P. Cho and Alan J. Cross and Steven S. Wesolowski and Andrew S. Felts and Jonas Bergare and Charles S. Elmore and Craig W. Lindsley and Colleen M. Niswender and P. Jeffrey Conn}, title = {Differential Pharmacology and Binding of mGlu2 Receptor Allosteric Modulators}, volume = {93}, number = {5}, pages = {526--540}, year = {2018}, doi = {10.1124/mol.117.110114}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Allosteric modulation of metabotropic glutamate receptor 2 (mGlu2) 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 mGlu2 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 mGlu2 allosteric modulators, we developed and characterized a novel mGlu2 positive allosteric modulator (PAM) radioligand in parallel with functional studies of a structurally diverse set of mGlu2 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 mGlu2, whereas NAMs predominantly affect the efficacy of glutamate in our assay system. More importantly, we found that binding of a novel mGlu2 PAM radioligand was inhibited by multiple structurally diverse PAMs and NAMs, indicating that they may bind to the mGlu2 allosteric site labeled with the novel mGlu2 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 mGlu2 allosteric modulators and suggest that different ligands either interact with distinct sites or adapt different binding poses to shared allosteric site(s).}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/93/5/526}, eprint = {https://molpharm.aspetjournals.org/content/93/5/526.full.pdf}, journal = {Molecular Pharmacology} }