Résumé
In the brain, group-III metabotropic glutamate (mGlu) receptors mGlu
4, mGlu
7 and mGlu
8 receptors play a critical role in controlling the release process at many glutamatergic synapses. The pharmacological profile of mGlu
4 receptor has been studied extensively, allowing us to propose a pharmacophore model for this receptor subtype. Surprisingly, the activity of only a few compounds have been reported on mGlu
7 and mGlu
8 receptors. In order to identify new possibilities for the design of selective compounds able to discriminate between the members of the group-III mGlu receptors, we have undertaken a complete pharmacological characterization of mGlu
8 receptor and compared it with that of mGlu
4 receptor, using the same expression system, and the same read out. The activities of 32 different molecules revealed that these two mGlu receptors subtypes share a similar pharmacological profile. Only small differences were noticed in addition to that previously reported with
S-carboxyglutamate (
S-Gla) being a partial agonist at mGlu
4 receptor and a full antagonist at mGlu
8 receptor. These include: a slightly higher relative potency of the agonists 1
S,3
R and 1
S,3
S-aminocyclopentane-1,3-dicarboxylic acid (ACPD),
S-4-carboxyphenylglycine (
S-4CPG) and
S-4-carboxy-3-hydroxyphenylglycine (
S-4C3HPG), and a slightly higher potency of the antagonists 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and
RS-α-methyl-4-phosphonophenylglycine (MPPG) on mGlu
8 receptor. When superimposed on the mGlu
4 receptor pharmacophore model, these molecules revealed three regions that may be different between the ligand binding sites of mGlu
8 and mGlu
4 receptors.