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
posted on 2020-07-06, 18:15authored byMatthew
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.