TY - JOUR
T1 - Revisiting the Quinoxalinedione scaffold in the Construction of New Ligands for the Ionotropic Glutamate Receptors.
AU - Demmer, Charles Sylvain
AU - Rombach, David
AU - Liu, Na
AU - Nielsen, Birgitte
AU - Pickering, Darryl S
AU - Bunch, Lennart
PY - 2017/11/15
Y1 - 2017/11/15
N2 - 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 among the AMPA, NMDA, and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogues are compound 2m being a high affinity ligand for native AMPA receptors (IC50= 0.48 μM), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and 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.
AB - 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 among the AMPA, NMDA, and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogues are compound 2m being a high affinity ligand for native AMPA receptors (IC50= 0.48 μM), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and 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.
U2 - 10.1021/acschemneuro.7b00243
DO - 10.1021/acschemneuro.7b00243
M3 - Journal article
C2 - 28872835
SN - 1948-7193
VL - 8
SP - 2477
EP - 2495
JO - A C S Chemical Neuroscience
JF - A C S Chemical Neuroscience
IS - 11
ER -