Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor:: Synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethyl-amine

This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g., 3) potentiate glutamate, shifting agonist potency by 2-fold. This effect was specific for mGlu2 (vs mGlu1,3-8 receptors). Also, 3 failed to potentiate a chimeric mGlu2/1 receptor, demonstrating the mGlu2 transmembrane region's critical involvement. In a fear-potentiated startle model, 3 showed anxiolytic activity that was prevented by mGlu2/3 antagonist pretreatment. Thus, these pyridylmethylsulfonamides represent the first mGlu2 receptor potentiators discovered.