Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

ACS Chem Neurosci. 2017 Aug 16;8(8):1681-1687. doi: 10.1021/acschemneuro.7b00117. Epub 2017 May 30.

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.

Keywords: Ionotropic glutamate receptor; NMDA; d-cycloserine; d-serine; subtype selectivity; superagonist.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / pharmacology*
  • Glycine / metabolism
  • Glycine / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Oocytes
  • Patch-Clamp Techniques
  • Protein Binding
  • Protein Multimerization
  • Receptors, N-Methyl-D-Aspartate / agonists*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Xenopus laevis

Substances

  • Excitatory Amino Acid Agonists
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Glycine