期刊
ACS CHEMICAL NEUROSCIENCE
卷 8, 期 11, 页码 2477-2495出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00243
关键词
Structure-activity relationship study; Ionotropic glutamate receptor ligands; amino acids; amino acid bioisoster
资金
- H. Lundbeck A/S
- Lundbeck Foundation
- Chinese Scholarship Council
More than two decades ago, the quinoxalinedione scaffold was shown to act as an alpha-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 mu M), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and compounds 2s,t,u are selective ligand for the GIuK1 receptor. Most interestingly, compound 2w was shown to be a GluK3-preferring ligand with full selectivity over native AMPA, KA and NMDA receptors.
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