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
  • 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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