Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from Traditional High Throughput Screening.

摘要: N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction thought contribute impairment observed both schizophrenia Alzheimer’s disease. One approach enhance function of increase concentration an coagonist, such as glycine or d-serine, synaptic cleft. Inhibition alanine–serine–cysteine transporter-1 (Asc-1), primary transporter attractive because localized neurons brain regions function, including hippocampus cortical layers III IV, colocalized with d-serine NMDARs. To identify novel Asc-1 inhibitors, two different screening approaches were performed whole-cell amino acid uptake heterologous cells stably expressing human Asc-1: (1) a high-throughput screen (HTS) 3 M compounds measuring 35S l-cysteine into attached sci...