@article {Rodriguezmol.110.067207, author = {Alice L. Rodriguez and Mark D. Grier and Carrie K. Jones and Elizabeth J. Herman and Alexander S. Kane and Randy L. Smith and Richard Williams and Ya Zhou and Joy E. Marlo and Emily L. Days and Tasha N. Blatt and Satyawan Jadhav and Usha N. Menon and Paige N. Vinson and Jerri M. Rook and Shaun R. Stauffer and Colleen M. Niswender and Craig W. Lindsley and C. David Weaver and P. Jeffrey Conn}, title = {Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity}, elocation-id = {mol.110.067207}, year = {2010}, doi = {10.1124/mol.110.067207}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders including anxiety and schizophrenia. While compounds have been developed to better understand the physiological roles of mGluR5 and potential utility for treatment of these disorders, there are limitations in tools available including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs). VU0285683 was developed as a novel selective mGluR5 NAM with high affinity for the MPEP binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate PCP-induced hyperlocomotor activity. VU0092273 was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, VU0360172, which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. Also, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in treatment of CNS disorders.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2010/10/05/mol.110.067207}, eprint = {https://molpharm.aspetjournals.org/content/early/2010/10/05/mol.110.067207.full.pdf}, journal = {Molecular Pharmacology} }