%0 Journal Article %A Colleen M Niswender %A Kari A Johnson %A Nicole R Miller %A Jennifer E Ayala %A Qingwei Luo %A Richard Williams %A Samir Saleh %A Darren Orton %A C. David Weaver %A P. Jeffrey Conn %T Context-dependent pharmacology exhibited by negative allosteric modulators of metabotropic glutamate receptor 7 %D 2010 %R 10.1124/mol.109.058768 %J Molecular Pharmacology %P mol.109.058768 %X Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of CNS disorders such as anxiety and depression. Suzuki et al. (Suzuki et al., 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called MMPIP, which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. As reported by Suzuki et al., we describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells co-expressing mGluR7 and the promiscuous G protein Gα15. Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative cooperativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous Gi/o-coupled assay readouts indicates that the pharmacology of these ligands appears to be context-dependent and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist LY341495, MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize coupling of this receptor to native Gi/o signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/early/2010/01/11/mol.109.058768.full.pdf