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J Med Chem
2020 Jul 23;6314:7569-7600. doi: 10.1021/acs.jmedchem.9b01733.
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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.
Epplin MP, Mohan A, Harris LD, Zhu Z, Strong KL, Bacsa J, Le P, Menaldino DS, Traynelis SF, Liotta DC.
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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.
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32538088 ???displayArticle.pmcLink???PMC7961853 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
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