Discovery of Dihydropyrrolo[1,2‑a]pyrazin-3(4H)‑one-Based Second-Generation GluN2C- and GluN2D-Selective Positive Allosteric Modulators (PAMs) of the N‑Methyl‑d‑Aspartate (NMDA) Receptor
datasetposted on 2020-07-06, 18:15 authored by Matthew P. Epplin, Ayush Mohan, Lynnea D. Harris, Zongjian Zhu, Katie L. Strong, John Bacsa, Phuong Le, David S. Menaldino, Stephen F. Traynelis, Dennis C. Liotta
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.
PAMincrease glutamate potency 2-glutamatergic synaptic transmissionGluN 2DGluN 2Cion channelsecond-generation GluN 2C NMDAR-pos...methyl-d-aspartate receptorlog unitGluN 2D NMDA receptors-1180-453Allosteric ModulatorsEUagonist 4-exhibits log unit improvementslipophilic efficiencyvivo toolspyrazinfirst-generation prototype CIQCNS disordersconcentrationreceptor response