Discovery of Dihydropyrrolo[1,2- a]pyrazin-3(4 H)-one-Based Second-Generation GluN2C- and GluN2D-Selective Positive Allosteric Modulators (PAMs) of the N-Methyl-d-Aspartate (NMDA) Receptor

J Med Chem. 2020 Jul 23;63(14):7569-7600. doi: 10.1021/acs.jmedchem.9b01733. Epub 2020 Jul 6.


The N-methyl-d-aspartate receptor (NMDAR) is an ion channel that mediates the slow, Ca2+-permeable component of glutamatergic synaptic transmission in the central nervous system (CNS). NMDARs are known to play a significant role in basic neurological functions, and their dysfunction has been implicated in several CNS disorders. Herein, we report the discovery of second-generation GluN2C/D-selective NMDAR-positive allosteric modulators (PAMs) with a dihydropyrrolo[1,2-a]pyrazin-3(4H)-one core. The prototype, R-(+)-EU-1180-453, exhibits log unit improvements in the concentration needed to double receptor response, lipophilic efficiency, and aqueous solubility, and lowers cLogP by one log unit compared to the first-generation prototype CIQ. Additionally, R-(+)-EU-1180-453 was found to increase glutamate potency 2-fold, increase the response to maximally effective concentration of agonist 4-fold, and the racemate is brain-penetrant. These compounds are useful second-generation in vitro tools and a promising step toward in vivo tools for the study of positive modulation of GluN2C- and GluN2D-containing NMDA receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Animals
  • Drug Design
  • Isoquinolines / chemical synthesis
  • Isoquinolines / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Molecular Structure
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Receptors, N-Methyl-D-Aspartate / agonists*
  • Structure-Activity Relationship
  • Xenopus laevis


  • Isoquinolines
  • NR2C NMDA receptor
  • NR2D NMDA receptor
  • Pyrazines
  • Pyrroles
  • Receptors, N-Methyl-D-Aspartate