A novel serine racemase inhibitor suppresses neuronal over-activation in vivo

作者：Mori Hisashi; Wada Ryogo; Takahara Satoyuki; Horino Yoshikazu; Izumi Hironori; Ishimoto Tetsuya; Yoshida Tomoyuki; Mizuguchi Mineyuki; Obita Takayuki; Gouda Hiroaki; Hirono Shuichi; Toyooka Naoki

来源：BIOORGANIC %26 MEDICINAL CHEMISTRY, 2017, 25(14): 3736-3745.

DOI：10.1016/j.bmc.2017.05.011

• Serine racemase
• D-Serine
• Arc-Luc Tg mice
• NMDA receptors
• Over-action
• In vivo assay

Serine racemase (SRR) is an enzyme that produces o-serine from L-serine. D-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and A beta peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states. In the previous study, we performed in silico screening to identify four compounds with inhibitory activities against recombinant SRR. Here, we synthesized 21 derivatives of candidate 1, one of four hit compounds, and performed screening by in vitro evaluations. The derivative 13J showed a significantly lower IC50 value in vitro, and suppressed neuronal over-activation in vivo.

• 出版日期2017-7-15