Therapeutic potential of non-competitive, subtype-selective metabotropic glutamate receptor ligands

Metabotropic glutamate (mGlu) receptors have progressively evolved from the status of a 'solution looking for problems' to being the focus of major drug discovery programmes in an increasing number of large pharmaceutical companies. The steady increase in interest for these targets was primarily due to their relatively recent discovery and consequently, to the lack of selective systemically-active ligands to allow precise assessment of their physiological role and therapeutical potential. Fortunately, strong faith in the potential of modulatory receptors of the major excitatory transmitters in the mammalian brain, glutamate, led tenacious pioneers to design molecules which have been extremely useful to Validate valuable targets for medicinal chemistry development. In addition, the increasing use of recently available high-throughput functional assays allowed the identification of ligands for these targets with novel mechanisms of action. This review will concentrate on recent progress in the field, focussing on novel pharmacological agents acting non-competitively as allosteric modulators of the mGlu receptors and on their potential use as therapeutic agents.