Subproject IV: Bioinformatics analyses of group-III metabotropic glutamate receptor structure-mechanism relationships

Glutamate neurotransmission plays fundamental roles in the central nervous system. Glutamate acts on ionotropic and metabotropic G-protein-coupled receptors (mGluRs). The latter appear as excellent targets for drug development since they modulate either pre- or post-synaptically glutamatergic transmission. Recent findings indicate that a group of mGluRs (specially mGluR4 and mGluR7) has beneficial effects in neuropathic and inflammatory pain. However, only very few compounds acting on these receptors have been identified so far. Thus, the aim of the project is to identify new compounds activating or modulating these receptors and evaluate their therapeutic potential. This project will be conducted by 4 teams: (1a) a molecular pharmacologist, responsible for the establishment of functional assays based on BRET and FRET and the pharmacological characterization of the compounds and (1b) an expert in the fundamental and clinical study of pain, responsible for the therapeutic assessment of selected compounds; (2) a chemist who will generate a library of analogs using combinatorial chemistry; (3) a yeast molecular biologist who will set up a screening assay based on the expression of these receptors in yeast; and (4) a bioinformatician who will generate models of the compounds in their binding sites for silico screening and drug design. This program will lead to the generation of new and original assays to identify mGluR ligands, will provide important new information on the mechanism of action of various types of molecules acting on these receptors, and will identify new compounds acting on mGluR4 and mGluR7 with beneficial actions in chronic pain.