Journal
FASEB JOURNAL
Volume 26, Issue 4, Pages 1682-1693Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-195941
Keywords
mGluR; drug development; Parkinson's disease
Categories
Funding
- Fondation pour la Recherche Medicale [INE20050303431]
- Agence Nationale pour la Recherche [ANR-05-NEUR-0121-04, ANR-07-NEURO-047-01, ANR-08-NEUR-006]
- CNRS (Direction de l'Innovation et des Relations avec les Entreprises)
- Ministere de l'Education Nationale, de la Recherche et de la Technologie
- Societe Francaise d'Etude et de Traitement de la Douleur
- Institut UPSA de la Douleur
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Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area. We report the properties of the first mGlu4-selective orthosteric agonist, derived from a virtual screening hit, LSP4-2022 using cell-based assays with recombinant mGlu receptors [EC50: 0.11 +/- 0.02, 11.6 +/- 1.9, 29.2 +/- 4.2 mu M (n>19) in calcium assays on mGlu4, mGlu7, and mGlu8 receptors, respectively, with no activity at the group I and -II mGlu receptors at 100 mu M]. LSP4-2022 inhibits neurotransmission in cerebellar slices from wild-type but not mGlu4 receptor-knockout mice. In vivo, it possesses antiparkinsonian properties after central or systemic administration in a haloperidol-induced catalepsy test, revealing its ability to cross the blood-brain barrier. Site-directed mutagenesis and molecular modeling was used to identify the LSP4-2022 binding site, revealing interaction with both the glutamate binding site and a variable pocket responsible for selectivity. These data reveal new approaches for developing selective, hydrophilic, and brain-penetrant mGlu receptor agonists, offering new possibilities to design original bioactive compounds with therapeutic potential.-Goudet, C., Vilar, B., Courtiol, T., Deltheil, T., Bessiron, T., Brabet, I., Oueslati, N., Rigault, D., Bertrand, H.-O., McLean, H., Daniel, H., Amalric, M., Acher, F., Pin, J.-P. A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype-selective ligands with therapeutic potential. FASEB J. 26, 1682-1693 (2012). www.fasebj.org
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