Revisiting the Quinoxalinedione scaffold in the Construction of New Ligands for the Ionotropic Glutamate Receptors.

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Charles Sylvain Demmer, David Rombach, Na Liu, Birgitte Nielsen, Darryl S Pickering, Lennart Bunch

More than two decades ago, the quinoxalinedione scaffold was shown to act as an α-amino acid bioisoster. Following extensive structure-activity-relationship (SAR) studies, the antagonists DNQX, CNQX, and NBQX in the ionotropic glutamate receptor field were identified. In this work we revisit the quinoxalinedione scaffold and explore the incorporation of an acid functionality in the 6-position. The SAR studies disclose that by this strategy it was possible to tune in iGluR selectivity amongst the AMPA, NMDA and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogs are compound 2m being a high affinity ligand for native AMPA receptors (IC50= 0.48 µM), analogs 2e,f,h,k,v all displayed selectivity for native NMDA receptors, compounds 2s,t,u are selective ligand for the GluK1 receptor. Most interestingly compound 2w was shown to be a GluK3-preferring ligand with full selectivity over native AMPA, KA and NMDA receptors.
Original languageEnglish
JournalA C S Chemical Neuroscience
Volume8
Issue number11
Pages (from-to)2477-2495
Number of pages19
ISSN1948-7193
DOIs
Publication statusPublished - 1 Dec 2017

ID: 182579722