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Accueil > Equipes de recherche > Pharmacochimie des récepteurs et des transporteurs des α-aminoacides > Thèmes de recherche

Class C G Protein Coupled Receptors (GPCRs)

publié le , mis à jour le

GPCRs make up the largest family of small molecule targets on the drug market. However these mostly belong to class A, although class C receptors are perceived as highly valuable new targets. Among these metabotropic glutamate receptors (mGluRs) are found. Glutamate is the major excitatory neurotransmitter in the brain. It activates ligand gated ion channels (ionotropic receptors, iGluRs) and mGluRs. The iGluRs are responsible of the fast synaptic transmission while mGluRs are modulators of that event. Accordingly mGluRs may allow a fine tuning that is required for CNS treatments. Class C GPCRs are characterized by a large amino terminal domain that folds in two lobes connected by a flexible hinge and named Venus Flytrap (VFT) domain. The agonist binding site is located in the cleft near the hinge. It has been demonstrated that the VFT domain needs to adopt a closed conformation that induces a movement of the receptor dimer in order to trigger activation and signal transduction.
Eight subtypes of mGluRs have been identified and classified in three groups (mGlu1-5 in group-I, mGlu2-3 in group-II and mGlu4-6-7-8 in group-III). Besides mGlu6 that is only present in the retina, group-III receptors are mostly presynaptic. Their activation will reduce the release of glutamate or GABA from hetero-receptors. We have been involved for many years in the development of group-III receptor orthosteric ligands and in activation mechanism investigation. We initially built a homology model of the VFT domain of mGlu4 docked L-AP4, a phosphonate analogue of glutamate that selectively activates group-III mGlu receptors. We then ran a virtual high through screening (vHTS) of the binding domain and discovered PCEP that was optimized in a series of analogues. PCEP allowed us to disclose a new binding pocket next to the glutamate binding site where in fact a chloride is bound. This new pocket is lined with selective residues which explains the mGlu4 selectivity of LSP4-2022 and will allow the design of other subtype selective orthosteric agonists.

We are currently pursuing the development of group-III selective ligands with the help of 3D-models. These compounds are tested in several in vivo models of neuropathologies such as pain, addiction and psychiatric diseases. Some of our group-III mGluR agonists (ACPT-I, LSP1-2111, LSP4-2022) have been evaluated in preclinical studies and show advantageous properties such as high aqueous solubility, brain penetration and metabolic stability.