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

The <i>N</i>-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-<i>a</i>]­pyrazin-3­(4<i>H</i>)-one core. The prototype, <i><b>R</b></i><b>-(+)-EU-1180-453</b>, 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 <b>CIQ</b>. Additionally, <i><b>R</b></i><b>-(+)-EU-1180-453</b> 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 <i>in vitro</i> tools and a promising step toward <i>in vivo</i> tools for the study of positive modulation of GluN2C- and GluN2D-containing NMDA receptors.