Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment.

A series of structurally novel GluN2B NMDAR antagonists were designed, synthesized, and biologically evaluated as anti-stroke therapeutics by optimizing the chemical structure of Pierardine, the active ingredient of traditional Chinese medicine Dendrobium aphyllum (Roxb.) C. E. Fischer identified via in silico screening. The systematic structure-activity relationship study led to the discovery of 58 with promising NMDAR-GluN2B binding affinity and antagonistic activity. Of the two enantiomers, S-58 exhibited significant inhibition (IC50 = 74.01 ± 12.03 nM) against a GluN1/GluN2B receptor-mediated current in a patch clamp assay. In addition, it displayed favorable specificity over other subtypes and off-target receptors. In vivo, S-58 exerted therapeutic efficacy comparable to that of the approved GluN2B NMDAR antagonist ifenprodil and excellent safety profiles. In addition to the attractive in vitro and in vivo potency, S-58 exhibited excellent brain exposure. In light of these merits, S-58 has been advanced to further preclinical investigation as a potential anti-stroke candidate.

Applicability of RANS models and pressure drop in edge subchannels for 19-pin wire-wrapped fuel bundle channel in CiADS.

The accelerator-driven subcritical system has a strong transmutation ability and high inherent safety, and it is internationally recognized as the most promising long-life nuclear waste disposal device. This study involves the construction of a Visual Hydraulic ExperimentaL Platform (VHELP) for the purpose of evaluating the applicability of Reynolds-averaged Navier-Stokes (RANS) models and analyzing the pressure distribution within the fuel bundle channel of China initiative accelerator-driven system (CiADS). Measurements of thirty differential pressures in edge subchannels within a 19-pin wire-wrapped fuel bundle channel were obtained under different conditions using deionized water. The pressure distribution in the fuel bundle channel at Reynolds numbers of 5000, 7500, 10,000, 12,500, and 15,000 was simulated using Fluent. The results show that RANS models obtained accurate results, and the shear stress transport k-ω model provided the most accurate prediction of the pressure distribution. The difference between the results of the Shear stress transport (SST) k-ω model and experimental data was the smallest, and the maximum difference was ±5.57%. Moreover, the error between the experimental data and numerical results of the axial differential pressure was smaller than that of the transverse differential pressure. The pressure periodicity in axial and transverse directions (one pitch) and a relatively three-dimensional pressure measurements were studied. The static pressure fluctuated and decreased periodically as the z-axis coordinate increased. These results can facilitate research on the cross-flow characteristics of liquid metal-cooled fast reactors.