Identification and in silicon binding study of a novel NR2B selective NMDAR antagonist.

Alzheimer's disease (AD) is a major group of diseases that threaten human health, and the search for drugs and treatments for it has never stopped. Research and development of NMDA receptor antagonists as potential therapeutic targets have also been ongoing. Our group designed and synthesized 22 new tetrahydropyrrolo[2,1-b]quinazolines based on NR2B-NMDARs targets and evaluated them for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, A21 exhibited excellent neuroprotective activity. Subsequently, the structure-activity relationships and inhibitor binding modes of the tetrahydropyrrolo[2,1-b]quinazolines were further analyzed by molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The results showed that A21 could match the two binding pockets of NR2B-NMDARs. The research results of this project will lay a certain foundation for the research of novel NR2B-NMDA receptor antagonists and also provide new ideas for the subsequent research and development of this target.

Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia.

A series of tryptamine derivatives has been designed and synthesized as novel GluN2B subunit-containing NMDA receptor (GluN2B-NMDAR) antagonists, which could simultaneously manifest the receptor-ligand interactions of representative GluN2B-NMDAR antagonists ifenprodil (1) and EVT-101 (3). In the present study, the neuroprotective potential of these compounds was explored through chemical synthesis and pharmacological characterization. Compound Z25 with significantly better neuroprotective activity than the positive control drug (percentage of protection: 55.8 ± 0.6% vs. 41.0 ± 2.7%) was considered to be an effective antagonist of the human GluN2B-NMDA receptor. Judging from in vitro pharmacological profiling, Z25 could downregulate NMDA-induced increased intracellular Ca2+ concentration, and Z25 could also upregulate NMDA-induced decreased intracellular p-ERK 1/2 expression, which suggested that Z25 is an antagonist of the GluN2B-NMDA receptor. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound Z25 showed remarkable plasma stability. Based on in vivo pharmacokinetic and pharmacodynamic studies in C57 mice, compound Z25 exhibited a relatively short half-life and a low F value (3.12 ± 0.01%), while administration of Z25 substantially improved the cognitive performance of mice in a series of tests of cerebral ischemic injury. Overall, these results support the further development of compound Z25 as a potential lead compound to treat the cerebral ischemic injury by antagonizing GluN2B-NMDA receptor.