Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists

Alex Maolanon, Athanasios Papangelis, David Kawiecki, Tung Chung Mou, Jed T. Syrenne, Feng Yi, Kasper B. Hansen, Rasmus P. Clausen

Research output: Contribution to journalArticlepeer-review

Abstract

We developed a versatile stereoselective route for the synthesis of new 2′-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2′-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2′-butyl-(S)-CCG-IV that determines the position of 2′-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications.

Original languageEnglish
Article number113099
JournalEuropean Journal of Medicinal Chemistry
Volume212
DOIs
StatePublished - Feb 15 2021

Keywords

  • (carboxycyclopropyl)glycine
  • NMDA
  • Synthesis
  • X-ray crystallography

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