Mori Hisashi, Wada Ryogo, Takahara Satoyuki, Horino Yoshikazu, Izumi Hironori, Ishimoto Tetsuya, Yoshida Tomoyuki, Mizuguchi Mineyuki, Obita Takayuki, Gouda Hiroaki, Hirono Shuichi, Toyooka Naoki
Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
Bioorg Med Chem. 2017 Jul 15;25(14):3736-3745. doi: 10.1016/j.bmc.2017.05.011. Epub 2017 May 11.
Serine racemase (SRR) is an enzyme that produces d-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 Aβ 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 IC value in vitro, and suppressed neuronal over-activation in vivo.
丝氨酸消旋酶（SRR）是一种将L-丝氨酸转化为D-丝氨酸的酶。D-丝氨酸作为N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体（NMDARs）的内源性协同激动剂，调节多种生理功能。NMDARs的过度激活会诱导兴奋性毒性，这在许多神经退行性疾病和癫痫状态中都有观察到。在我们之前关于SRR基因敲除（Srr-KO）小鼠的生成及其对NMDA和Aβ肽诱导的神经退行性变的保护作用的研究中，我们假设通过抑制SRR活性来调节NMDARs的过度激活是对抗这些疾病状态的一种治疗策略。在之前的研究中，我们进行了计算机筛选，以鉴定出四种对重组SRR具有抑制活性的化合物。在此，我们合成了四种活性命中化合物之一的候选化合物1的21种衍生物，并通过体外评估进行筛选。衍生物13J在体外显示出显著更低的半数抑制浓度（IC）值，并在体内抑制了神经元的过度激活。
