Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity

Fabao Zhao, Georgios Mazis, Feng Yi, James S. Lotti, Michael S. Layeux, Eric P. Schultz, Lennart Bunch, Kasper B. Hansen, Rasmus P. Clausen

Research output: Contribution to journalArticlepeer-review

Abstract

N-Methyl-d-aspartate (NMDA) receptors play critical roles in central nervous system function and are involved in variety of brain disorders. We previously developed a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid glycine site agonists with pronounced variation in activity among NMDA receptor GluN1/2A-D subtypes. Here, a series of (R)-2-amino-3-triazolpropanoic acid analogues with a novel chemical scaffold is designed and their pharmacological properties are evaluated at NMDA receptor subtypes. We found that the triazole can function as a bioisostere for amide to produce glycine site agonists with variation in activity among NMDA receptor subtypes. Compounds 13g and 13i are full and partial agonists, respectively, at GluN1/2C and GluN1/2D with 3- to 7-fold preference in agonist potency for GluN1/2C-D over GluN1/2A-B subtypes. The agonist binding mode of these triazole analogues and the mechanisms by which the triazole ring can serve as a bioisostere for amide were further explored using molecular dynamics simulations. Thus, the novel (R)-2-amino-3-triazolpropanoic acid derivatives reveal insights to agonist binding at the GluN1 subunit of NMDA receptors and provide new opportunities for the design of glycine site agonists.

Original languageEnglish
Article number1008233
JournalFrontiers in Chemistry
Volume10
DOIs
StatePublished - Nov 17 2022

Keywords

  • co-agonist
  • ionotropic glutamate receptors
  • ligand-gated ion channel
  • subtype selectivity
  • two-electrode voltage-clamp electrophysiology

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