20-oxo-5α-pregnan-3α-yl hemisuccinate | 148346-36-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 20-oxo-5α-pregnan-3α-yl hemisuccinate
• 英文别名: 4-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-4-oxobutanoic acid
• CAS: 148346-36-5
• 化学式: C₂₅H₃₈O₅
• 分子量: 418.574
• InChiKey: UVTGFMKBPVLATL-LUPVOPLESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  80.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  丁二酸酐 、 5alpha-孕甾-3alpha-醇-20-酮 在 4-二甲氨基吡啶 作用下， 以 吡啶 为溶剂， 反应 7.0h， 以53%的产率得到20-oxo-5α-pregnan-3α-yl hemisuccinate
  参考文献：
  名称：

  Synthesis of C3, C5, and C7 pregnane derivatives and their effect on NMDA receptor responses in cultured rat hippocampal neurons

  摘要：

  The synthesis of several novel 5 alpha- and 5 beta-20-oxo-pegnane derivatives substituted in the position 3 and 7 of the steroid skeleton is described. Activity of synthesized compounds was studied in voltage-clamped cultured rat hippocampal neurons. Substituted derivatives inhibited NMDA-elicited neuronal activity. The relationship between biological activity and structure is discussed. (C) 2008 Published by Elsevier Inc.

  DOI：

  10.1016/j.steroids.2008.11.011

文献信息

• Pregnane‐based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss‐of‐function disease‐associated <i>GRIN</i> mutations
  作者：Bohdan Kysilov、Barbora Hrcka Krausova、Vojtech Vyklicky、Tereza Smejkalova、Miloslav Korinek、Martin Horak、Hana Chodounska、Eva Kudova、Jiri Cerny、Ladislav Vyklicky

  DOI：10.1111/bph.15841

  日期：2022.8

  Background and PurposeN‐methyl‐D‐aspartate receptors (NMDARs) play a critical role in synaptic plasticity, and mutations in human genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. Compounds with a positive allosteric effect are thought to compensate for reduced receptor function.Experimental ApproachWe have used whole‐cell patch‐clamp electrophysiology on recombinant rat NMDARs and human variants found in individuals with neuropsychiatric disorders, in combination with in silico modelling, to explore the site of action of novel epipregnanolone‐based NMDAR modulators.Key ResultsAnalysis of the action of 4‐(20‐oxo‐5β‐pregnan‐3β‐yl) butanoic acid (EPA‐But) at the NMDAR indicates that the effect of this steroid with a “bent” structure is different from that of cholesterol and oxysterols and shares a disuse‐dependent mechanism of NMDAR potentiation with the “planar” steroid 20‐oxo‐pregn‐5‐en‐3β‐yl sulfate (PE‐S). The potentiating effects of EPA‐But and PE‐S are additive. Alanine scan mutagenesis identified residues that reduce the potentiating effect of EPA‐But. No correlation was found between the effects of EPA‐But and PE‐S at mutated receptors that were less sensitive to either steroid. The relative degree of potentiation induced by the two steroids also differed in human NMDARs carrying rare variants of hGluN1 or hGluN2B subunits found in individuals with neuropsychiatric disorders, including intellectual disability, epilepsy, developmental delay, and autism spectrum disorder.Conclusion and ImplicationsOur results show novel sites of action for pregnanolones at the NMDAR and provide an opportunity for the development of new therapeutic neurosteroid‐based ligands to treat diseases associated with glutamatergic system hypofunction.