GPCRs have proven to be a valuable target family for drug discovery and development with more than 30% of marketed drugs acting through this receptor superfamily. However, numerous GPCR members remain challenging with no selective and druggable ligands being successfully developed. For these difficult targets, a novel strategy consisting in developing allosteric modulators (AMs) is now emerging. AMs positively or negatively modulate GPCR activity through interaction with binding sites topologically distinct from the orthosteric binding sites.Metabotropic glutamate receptors (mGluRs) belong to family C GPCRs and are characterized by a large extra-cellular domain named the �Venus flytrap� containing the orthosteric binding site and a 7TM domain where allosteric modulators bind. mGluRs represent attractive drug targets for numerous indications such as neurodegenerative or psychiatric disorders. They are divided into three groups based on their structures, signal transductions and pharmacologies.AMs of group II mGluRs (mGluR2 and mGluR3) are currently studied to discover new treatments for schizophrenia or anxiety (mGluR2 PAM), Alzheimer disease or depression (mGluR2/3 NAM), Parkinson disease (mGluR3 PAM) and glioblastoma (mGluR3 NAM). The development and screening of a FRET-based binding assay at Domain led to the identification of a novel family of mGluR2/3 NAMs. Medicinal chemistry efforts including molecular switch strategy (subtle structural modifications leading to drastic changes in the pharmacology), enable the discovery of novel families of selective mGluR2 NAMs, mGluR3 PAMs and mGluR3 NAMs.

Molecular switch strategy delivers distinct group II mGluR allosteric modulator families

246th National Meeting (2013)

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