A series of mono-, di-, tri-, and tetrasubstituted 1,4-dihydroquinoxaline-2,3-diones (QXs) were synthesized and evaluated as antagonists at N-methyl-D-aspartate (NMDA)/glycine sites and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-preferring non-NMDA receptors. Antagonist potencies were measured by electrical assays in Xenopus oocytes expressing rat whole brain poly(A)+ RNA. Trisubstituted QXs 17a (ACEA 1021), 17b (ACEA 1031), 24a, and 27, containing a nitro group in the 5 position and halogen in the 6 and 7 positions, displayed high potency (Kb approximately 6-8 nM) at the glycine site, moderate potency at non-NMDA receptors (Kb = 0.9-1.5 microM), and the highest (120-250-fold) selectivity in favor of glycine site antagonism over non-NMDA receptors. Tetrasubstituted QXs 17d,e were more than 100-fold weaker glycine site antagonists than the corresponding trisubstituted QXs with F being better tolerated than Cl as a substituent at the 8 position. Di- and monosubstituted QXs showed progressively weaker antagonism compared to trisubstituted analogues. For example, removal of the 5-nitro group of 17a results in a approximately 100-fold decrease in potency (10a,b,z), while removal of both halogens from 17a results in a approximately 3000-fold decrease in potency (10v). In terms of steady-state inhibition, most QX substitution patterns favor antagonism at NMDA/glycine sites over antagonism at non-NMDA receptors. Among the QXs tested, only 17i was slightly selective for non-NMDA receptors.
Alloys that have high strengths at high
temperatures are crucial for a variety of
important industries including aerospace. Alloys
with ordered superlattice structures are
attractive for this purpose but generally suffer
from poor ductility and rapid grain coarsening. We
discovered that nanoscale disordered interfaces
can effectively overcome these problems.
Interfacial disordering is driven by multielement
cosegregation that creates a distinctive nanolayer
between adjacent micrometer-scale superlattice
grains. This nanolayer acts as a sustainable
ductilizing source, which prevents brittle
intergranular fractures by enhancing dislocation
mobilities. Our superlattice materials have
ultrahigh strengths of 1.6 gigapascals with
tensile ductilities of 25% at ambient temperature.
Simultaneously, we achieved negligible grain
coarsening with exceptional softening resistance
at elevated temperatures. Designing similar
nanolayers may open a pathway for further
optimization of alloy properties.
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