2. Academic Validation
  3. Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

  • J Med Chem. 2018 Mar 8;61(5):1969-1989. doi: 10.1021/acs.jmedchem.7b01438.
Chelliah Selvam 1,  Isabelle A Lemasson 1,  Isabelle Brabet 2,  Nadia Oueslati 2,  Berin Karaman 1,  Alexandre Cabaye 1,  Amélie S Tora 2,  Bruno Commare 1 3,  Tiphanie Courtiol 1,  Sara Cesarini 1,  Isabelle McCort-Tranchepain 1,  Delphine Rigault 1,  Laetitia Mony 1 4,  Thomas Bessiron 5,  Heather McLean 5,  Frédéric R Leroux 3,  Françoise Colobert 3,  Hervé Daniel 5,  Anne Goupil-Lamy 6,  Hugues-Olivier Bertrand 6,  Cyril Goudet 2,  Jean-Philippe Pin 2,  Francine C Acher 1
Affiliations

Affiliations

  • 1 Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques , CNRS UMR 8601, Université Paris Descartes, Sorbonne Paris Cité , 45 rue des Saints-Pères , 75270 Paris Cedex 06 , France.
  • 2 IGF , CNRS, INSERM, Université Montpellier , F-34094 Montpellier , France.
  • 3 UMR 7509/CNRS/ECPM, Université de Strasbourg , 25 Rue Becquerel , 67087 Strasbourg 02 , France.
  • 4 Institut de Biologie , Ecole Normale Supérieure, CNRS UMR 8197, INSERM U1024, PSL University , 46 rue d'Ulm , 75005 Paris , France.
  • 5 Pharmacologie et Biochimie de la Synapse , Université Paris-Sud/CNRS/NeuroPSI-UMR 9197 , F-91405 Orsay , France.
  • 6 BIOVIA , Dassault Systèmes , 10 rue Marcel Dassault, CS 40501 , 78946 Vélizy-Villacoublay Cedex , France.
PMID: 29397723 DOI: 10.1021/acs.jmedchem.7b01438
Abstract

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.

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