1-ethyl-[(3R,4R)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one | 1019207-64-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-ethyl-[(3R,4R)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one
• 英文别名: 1-ethyl-3-(3-hydroxymethyl-4-piperidinyl)-1,3-dihydrobenzimidazol-2-one
• CAS: 1019207-64-7
• 化学式: C₁₅H₂₁N₃O₂
• 分子量: 275.351
• InChiKey: HTNFCQYJDIYYML-NWDGAFQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.97
• 重原子数：
  20.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  59.19
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  1-ethyl-[(3R,4R)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one 、 环辛烷甲醛 在 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 为溶剂， 反应 60.0h， 以42%的产率得到1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
  参考文献：
  名称：

  A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay

  摘要：

  A new chiral synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benziinidazol-2-one (2, J-113397) was developed. J-113397 has a K-e = 0.85 nM in an ORL-1 calcium mobilization assay and is 89-, 887-, and 227-fold selective for the ORL-1 receptor relative to the p, 6, and K opioid receptors. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.10.023
• 作为产物：
  描述：

  (3R,4R)-3-(tert-butyldimethylsilanyloxymethyl)-4-(3-ethyl-2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以76%的产率得到1-ethyl-[(3R,4R)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one
  参考文献：
  名称：

  A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay

  摘要：

  A new chiral synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benziinidazol-2-one (2, J-113397) was developed. J-113397 has a K-e = 0.85 nM in an ORL-1 calcium mobilization assay and is 89-, 887-, and 227-fold selective for the ORL-1 receptor relative to the p, 6, and K opioid receptors. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.10.023

文献信息

• Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor
  作者：Steven D. Chang、S. Wayne Mascarella、Skylar M. Spangler、Vsevolod V. Gurevich、Hernan A. Navarro、F. Ivy Carroll、Michael R. Bruchas

  DOI：10.1124/mol.115.099150

  日期：2015.9

  Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein–coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays, we identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G protein and arrestin pathways) to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands on the basis of NOPR antagonist J-113,397 [(±)-1-[(3 R *,4 R *)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2 H -benzimidazol-2-one] to explore structure-activity relationships. Our study shows that NOPR is capable of biased signaling, and further, the NOPR selective ligands MCOPPB [1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-(3 R )-3-piperidinyl-1 H -benzimidazole trihydrochloride] and NNC 63-0532 [8-(1-naphthalenylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-3-acetic acid, methyl ester] are G protein–biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor.

  对 G 蛋白偶联受体（GPCR）系统进行综合研究，将选择性配体、G 蛋白与停滞素-2/3 偶联的定量比较以及结构-活性关系模型结合起来，但这种研究较少采用。在这里，我们研究了阿片受体家族中最新发现的成员--神经痛素/表素 FQ 阿片受体（NOPR）的偏向信号传导。我们利用实时活细胞测定法确定了几种 NOPR 选择性配体在上游 GPCR 信号转导（G 蛋白和 arrestin 通路）中的信号转导特征，以确定它们的相对转导系数和信号转导偏差。作为这一分析的补充，我们在 NOPR 拮抗剂 J-113,397 [(±)-1-[(3 R *,4 R *)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2 H -benzimidazol-2-one] 的基础上设计了新型配体，以探索结构-活性关系。我们的研究表明，NOPR 具有偏向信号传导的能力。此外，NOPR 选择性配体 MCOPPB [1-[1-(1- 甲基环辛基)-4-哌啶基]-2-(3 R )-3- 哌啶基-1 H -苯并咪唑三盐酸盐] 和 NNC 63-0532 [8-(1-naphthalenylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]癸烷-3-乙酸甲酯]是偏向 G 蛋白的激动剂。此外，J-113,397 的微小结构修饰可使信号从拮抗剂活性显著转变为部分激动剂活性。我们通过结合位置的硅学建模来探索这些发现。这项研究首次证明了神经肽阿片受体的功能选择性和偏向配体的鉴定。