Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites
Chelliah Selvam
(1, 2, 3)
,
Isabelle Lemasson
(1, 2, 3)
,
Isabelle Brabet
(4)
,
Nadia Oueslati
(4)
,
Berin Karaman
(1, 2, 3)
,
Alexandre Cabaye
(1, 2, 3)
,
Amélie S. Tora
(4)
,
Bruno Commare
(1, 2, 3)
,
Tiphanie Courtiol
(1, 2, 3)
,
Sara Cesarini
(1, 2, 3)
,
Isabelle Mccort
(1, 2, 3)
,
Delphine Rigault
(1, 2, 3)
,
Laetitia Mony
(1, 5, 2, 3)
,
Thomas Bessiron
(6)
,
Heather Mclean
(6)
,
Frédéric Leroux
(7)
,
Françoise Colobert
(7)
,
Hervé Daniel
(6)
,
Anne Goupil-Lamy
(8)
,
Hugues-Olivier Bertrand
(8)
,
Cyril Goudet
(4)
,
Jean-Philippe Pin
(4)
,
Francine Acher
(1, 2, 3)
1
LCBPT - UMR 8601 -
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
2 UPD5 - Université Paris Descartes - Paris 5
3 USPC - Université Sorbonne Paris Cité
4 IGF - Institut de Génomique Fonctionnelle
5 IBENS - Institut de biologie de l'ENS Paris
6 NeuroPSI - Institut des Neurosciences Paris-Saclay
7 LCM - Laboratoire de chimie moléculaire
8 Dassault Systèmes
2 UPD5 - Université Paris Descartes - Paris 5
3 USPC - Université Sorbonne Paris Cité
4 IGF - Institut de Génomique Fonctionnelle
5 IBENS - Institut de biologie de l'ENS Paris
6 NeuroPSI - Institut des Neurosciences Paris-Saclay
7 LCM - Laboratoire de chimie moléculaire
8 Dassault Systèmes
Nadia Oueslati
- Fonction : Auteur
- PersonId : 760259
- IdRef : 183133072
Alexandre Cabaye
- Fonction : Auteur
- PersonId : 751412
- IdHAL : alexandre-cabaye
- ORCID : 0000-0002-2461-2082
Isabelle Mccort
- Fonction : Auteur
- PersonId : 749718
- IdHAL : isabelle-mccort-tranchepain
Françoise Colobert
- Fonction : Auteur
- PersonId : 771532
- ORCID : 0000-0003-4730-9868
- IdRef : 06045654X
Hervé Daniel
- Fonction : Auteur
- PersonId : 937694
- IdHAL : herve-daniel
- ORCID : 0000-0003-1522-9556
Cyril Goudet
- Fonction : Auteur
- PersonId : 182108
- IdHAL : cyril-goudet
- ORCID : 0000-0002-8255-3535
- IdRef : 162209274
Jean-Philippe Pin
- Fonction : Auteur
- PersonId : 742096
- IdHAL : jean-philippe-pin
- ORCID : 0000-0002-1423-345X
- IdRef : 033123152
Francine Acher
- Fonction : Auteur
- PersonId : 760258
- ORCID : 0000-0002-5413-4181
- IdRef : 067714560
Résumé
A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.