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Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure–Activity Relationship Study of Steroidal 3-Hemiesters
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-30 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00255
Barbora Krausova 1 , Barbora Slavikova 2 , Michaela Nekardova 2, 3 , Pavla Hubalkova 1, 4 , Vojtech Vyklicky 1 , Hana Chodounska 2 , Ladislav Vyklicky 1 , Eva Kudova 2
Affiliation  

Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure–activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 μM and Emax varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABAAR responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

中文翻译:

N-甲基-d-天冬氨酸受体的正调节剂:甾体3-半酯的结构-活性关系研究。

这里,我们报告孕甾-5-烯和雄甾-5-烯二羧酸酯的合成中,探索其的调制的结构-活性关系(SAR)ñ甲基d天冬氨酸受体(NMDAR的)。所有化合物均为重组GluN1 / GluN2B受体的正调节剂(EC 50为1.8至151.4μM ,E max为48%至452%)。此外,发现10种化合物比内源性孕烯醇酮硫酸盐更有效地发挥GluN1 / GluN2B受体调节剂的作用(EC 50= 21.7μM)。SAR研究揭示了类固醇分子碳C-3处的残基长度与GluN1 / GluN2B受体对各种D环修饰的正调节作用之间的关系。选定的化合物20-氧-孕烯醇酮半己酸酯能使天然NMDAR增强程度与GluN1 / GluN2A-D受体相似,并抑制AMPAR和GABA A R反应。这些结果为开发新的基于类固醇的药物提供了独特的机会,该药物可潜在地用于治疗涉及NMDAR功能低下的神经精神疾病。
更新日期:2018-04-30
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