Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure–Activity Relationship Study of Steroidal 3-Hemiesters,Journal of Medicinal Chemistry

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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 E_max 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 GABA_AR 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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