Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

Alex R. Maolanon, Rune Risgaard, Shuang Yan Wang, Yoran Snoep, Athanasios Papangelis, Feng Yi, David Holley, Anne F. Barslund, Niels Svenstrup, Kasper B. Hansen, Rasmus P. Clausen

Research output: Contribution to journalArticlepeer-review

Abstract

A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

Original languageEnglish
Pages (from-to)1681-1687
Number of pages7
JournalACS Chemical Neuroscience
Volume8
Issue number8
DOIs
StatePublished - Aug 16 2017

Keywords

  • Ionotropic glutamate receptor
  • NMDA
  • d -cycloserine
  • d -serine
  • subtype selectivity
  • superagonist

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