Progress in the Developement of Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2

A.      A. Trabanco; J.      M. Cid; H.      Lavreysen; G.      J. Macdonald; G.      Tresadern

Abstract

The metabotropic glutamate type 2 (mGlu2) receptor is a G-protein coupled receptor (GPCR) expressed on presynaptic nerve terminals where it negatively modulates glutamate and GABA release. Mixed mGlu2/mGlu3 orthosteric agonists such as LY354740 have shown activity in a range of preclinical animal models of anxiety and schizophrenia. Clinical work with LY354740 demonstrated activity in a CO2 inhalation study suggesting application in the treatment of anxiety related disorders. Subsequently, a related prodrug LY2140023 demonstrated improvements in positive and negative symptoms in patients suffering from schizophrenia. These molecules exhibit combined mGlu2/mGlu3 activity although there is evidence from knock-out studies that preclinical anti-psychotic effects may be mediated via the mGlu2 receptor. An alternative avenue for modulating GPCRs is to act via allosteric mechanisms, binding at a different site from the orthosteric agonist. Since the first discovery of mGlu2 positive allosteric modulators (PAMs) such as 2,2,2-TEMPS and BINA, multiple families of mGlu2 modulators have been reported and several have entered into clinical development. This review focuses on recent advances in the development of novel mGlu2 PAMs by analysis of compounds disclosed in research articles and patent literature between 2007 and 2010.

Keywords: Allosteric, metabotropic glutamate receptor, mGlu, mGluR, modulator, PAM, Glutamate, neurotransmitter, nervous system (CNS), vertebrates, synaptic responses, ionotropic glutamate (iGlu), pathophysiology, anxiety, schizophrenia, prefrontal cortex, hippocampus, anxiolytic, antipsychotic effects, nanomolar potent, amphetamine, rationale, prolactin levels, anxiolytic effects, ALLOSTERIC MODULATORS, antipsychotic activity, agonistic drugs, tolerance development, receptor signaling, affinity modulation, agonism, nanomolar activity, efficacy, acyclic acetophenones, acetophenone, antipsychotic, anxiolytic activity, Pharmaceuticals, isoindolone derivatives, psychiatric disorders, Prous Science Integrity, principal component analysis (PCA), chemotypes, amino acid like, oxazolobenzimidazoles, molecular weight, lipophilic, Acetophenones, antidepressant, Benzimidazoles, lipophilic substituents, halogens, alkyls, Cyclic Carbamates, asymmetric center, solubilizing, spirocyclic cyclohexyl group, polarity, cyclic carbamate, Imidazopyridines, bioisosteric, electrostatic, microsomes, incubation, Isoindolones, pyrazine, chirality, stereochemistry, oxazolidinone, pyrimidone, asymmetric, Pyridones, patent