Adla Santosh Kumar, Slavikova Barbora, Smidkova Marketa, Tloustova Eva, Svoboda Martin, Vyklicky Vojtech, Krausova Barbora, Hubalkova Pavla, Nekardova Michaela, Holubova Kristina, Vales Karel, Budesinsky Milos, Vyklicky Ladislav, Chodounska Hana, Kudova Eva
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
Steroids. 2017 Jan;117:52-61. doi: 10.1016/j.steroids.2016.08.010. Epub 2016 Aug 17.
Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-d-aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) - the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC=1.0 and 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC=24.6μM) and pregnanolone glutamate (IC=51.7μM); (ii) physicochemical properties (logP and logD) were calculated; (iii) Caco-2 assay revealed that the permeability properties of compounds 2 and 4 are comparable with pregnanolone glutamate; (iv) compounds 1-4 have minimal or no adverse hepatic effect; (v) compounds 1-4 cross blood-brain-barrier.
在此，我们报道了一类新型的基于酰胺的N-甲基-D-天冬氨酸受体（NMDARs）抑制剂（1-4），它们是作为硫酸孕烷醇酮（PAS）和谷氨酸孕烷醇酮（PAG）（甾体类神经保护性NMDAR抑制剂）的类似物制备而成。进行了一系列实验以评估它们的物理化学和生物学性质：（i）与内源性抑制剂硫酸孕烷醇酮（IC = 24.6μM）和谷氨酸孕烷醇酮（IC = 51.7μM）相比，化合物3和4对NMDARs的抑制作用显著提高（分别为IC = 1.0和1.4μM）；（ii）计算了物理化学性质（logP和logD）；（iii）Caco-2测定表明化合物2和4的渗透性与谷氨酸孕烷醇酮相当；（iv）化合物1-4具有最小的或没有不良肝脏影响；（v）化合物1-4可穿过血脑屏障。
