Stereoselective Synthesis of New (2 S,3 R)-3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid Analogues Utilizing a C(sp3)-H Activation Strategy and Structure-Activity Relationship Studies at the Ionotropic Glutamate Receptors

Silke Kayser, Jacob C. Hansen, Markus Staudt, Aleksandra Moroz, Younes Larsen, Piero Temperini, Feng Yi, Jed T. Syrenne, Niels Krogsgaard-Larsen, Stylianos Iliadis, Birgitte Nielsen, Kasper B. Hansen, Darryl S. Pickering, Lennart Bunch

Research output: Contribution to journalArticlepeer-review

Abstract

Competitive antagonists for ionotropic glutamate receptors (iGluRs) are highly valuable tool compounds for studying health and disease states in the central nervous system. However, only few subtype selective tool compounds are available and the discovery of antagonists with novel iGluR subtype selectivity profiles remains a profound challenge. In this paper, we report an elaborate structure-activity relationship (SAR) study of the parental scaffold 2,3-trans-3-carboxy-3-phenyl-proline by the synthesis of 40 new analogues. Three synthetic strategies were employed with two new strategies of which one being a highly efficient and fully enantioselective strategy based on C(sp3)-H activation methodology. The SAR study led to the conclusion that selectivity for the NMDA receptors was a general trend when adding substituents in the 5′-position. Selective NMDA receptor antagonists were obtained with high potency (IC50 values as low as 200 nM) and 3-34-fold preference for GluN1/GluN2A over GluN1/GluN2B-D NMDA receptors.

Original languageEnglish
Pages (from-to)674-701
Number of pages28
JournalACS Chemical Neuroscience
Volume11
Issue number5
DOIs
StatePublished - Mar 4 2020

Keywords

  • C(sp3)-H activation
  • Electrophysiology
  • Ionotropic glutamate receptors
  • NMDA receptor antagonist
  • Proline analogues

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