title: mGlu5 receptor antagonists: a novel class of anxiolytics?
abstract: In the early 1990s, a new family of receptors were cloned that were found to mediate the intracellular metabolic effects of glutamate via coupling to secondary messenger systems, that is, the metabotropic glutamate (mGlu) receptors. Eight such receptors (mGlu1 to mGlu8) have been cloned to date, and according to their amino acid sequence, pharmacology and second-messenger coupling, these receptors have been clustered into three groups (I-III). In contrast to the glutamate-gated ion channels (NMDA, AMPA and kainate receptors), which are responsible for fast excitatory transmission, mGlu receptors have been shown to play a modulatory role in the glutamatergic synaptic transmission either by modulating the ion channel activity or by influencing neurotransmitter release. Given the fact that the mGlu receptors are G-protein- coupled, they obviously constitute a new attractive group of "drugable" targets for the treatment of various CNS disorders. The recent discovery of small molecules that selectively bind to receptors of group I (mGlu1 and mGlu5) and group II (mGlu2 and mGlu3) allowed significant advances in our understanding of the roles of these receptors in brain physiology and pathophysiology. The identification of MPEP (2-methyl-6-(phenylethynyl)-pyridine), a highly selective and brain-penetrant mGlu5 receptor antagonist, allowed the exploration of the therapeutic potential of this class of compounds. Subsequent behavior studies revealed that--with the exception of benzodiazepines--mGlu5 receptor antagonists exhibit the widest and most robust anxiolytic activity in preclinical models seen to date. Upcoming clinical studies will soon indicate if the preclinical anxiolytic-like efficacy translates into anxiolytic activity in humans.
authors.affiliation: F. Hoffmann-La Roche, Pharma Research Basel Discovery, Neuroscience, Basel, Switzerland. will.spooren@roche.com
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D001665:Binding Sites / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D011725:Pyridines / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine