Abstract
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.
MeSH terms
-
Allosteric Regulation
-
Animals
-
Anti-Anxiety Agents / chemical synthesis*
-
Anti-Anxiety Agents / chemistry
-
Anti-Anxiety Agents / pharmacology
-
Calcium / metabolism
-
Cells, Cultured
-
Drug Synergism
-
Excitatory Amino Acid Agonists / pharmacology
-
Humans
-
Kinetics
-
Pyridines / chemical synthesis*
-
Pyridines / chemistry
-
Pyridines / pharmacology
-
Rats
-
Receptors, Metabotropic Glutamate / agonists
-
Receptors, Metabotropic Glutamate / antagonists & inhibitors
-
Receptors, Metabotropic Glutamate / drug effects*
-
Reflex, Startle / drug effects
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis*
-
Sulfonamides / chemistry
-
Sulfonamides / pharmacology
Substances
-
Anti-Anxiety Agents
-
Excitatory Amino Acid Agonists
-
N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine
-
N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide
-
Pyridines
-
Receptors, Metabotropic Glutamate
-
Sulfonamides
-
metabotropic glutamate receptor 2
-
Calcium