{4'-[3-((2R,5R)-dimethyl-3,4-di[3H]-pyrrolidin-1-yl)propoxy]biphenyl-4-yl}(morpholin-4-yl)methanone

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: {4'-[3-((2R,5R)-dimethyl-3,4-di[3H]-pyrrolidin-1-yl)propoxy]biphenyl-4-yl}(morpholin-4-yl)methanone
• 英文别名: [4-[4-[3-[(2R,5R)-2,5-dimethyl-3,4-ditritiopyrrolidin-1-yl]propoxy]phenyl]phenyl]-morpholin-4-ylmethanone
• 化学式: C₂₆H₃₄N₂O₃
• 分子量: 426.552
• InChiKey: CFUHKRLMDNFZED-SWHHKHQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  42
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  {4'-[3-((2R,5R)-dimethyl-2,5-dihydropyrrol-1-yl)propoxy]biphenyl-4-yl}(morpholin-4-yl)methanone 在 palladium on activated charcoal 超重氢 作用下， 以 乙酸乙酯 为溶剂， 反应 2.5h， 生成 {4'-[3-((2R,5R)-dimethyl-3,4-di[3H]-pyrrolidin-1-yl)propoxy]biphenyl-4-yl}(morpholin-4-yl)methanone
  参考文献：
  名称：

  Detection of multiple H₃ receptor affinity states utilizing [³ H]A-349821, a novel, selective, non-imidazole histamine H₃ receptor inverse agonist radioligand

  摘要：

  A-349821是一种选择性的组胺H3受体拮抗剂/反激动剂。在此，我们研究并比较了新型非咪唑类H3受体放射配体[3H]A-349821与激动剂[3H]N-α-甲基组胺（[3H]NαMH）在表达内源性或重组H3受体的来自大鼠或人类来源的膜中的结合特性。[3H]A-349821以高亲和力和特异性结合到一个明显的单类的可饱和位点，并且与大鼠H3受体相比，其识别人类H3受体的亲和力高了10倍。[3H]A-349821识别的受体数量比[3H]NαMH多。3H]A-349821结合的被H3受体拮抗剂/反激动剂置换的曲线为单相，提示识别单个结合位点，而H3受体激动剂的置换曲线为双相，提示识别高亲和力和低亲和力的H3受体位点。高亲和力结合位点的H3受体竞争剂的pKi值在使用[3H]A-349821时与使用[3H]NαMH获得的pKi值高度相关，这与[3H]A-349821标记H3受体一致。与使用[3H]NαMH的测定不同，加入GDP对使用[3H]A-349821测定的饱和参数没有影响，而[3H]A-349821结合被H3受体激动剂组胺置换对GDP敏感。结论：[3H]A-349821标记可相互转换的高亲和力和低亲和力的H3受体状态，并且与含有咪唑的H3受体拮抗剂放射配体相比，显示出改进的选择性。[3H]A-349821竞争性结合研究表明，高亲和力和低亲和力位点的比例和效力在不同物种之间存在显著差异，这为H3受体的基本药理性质提供了新信息。英国药理学杂志 (2006) 148, 657–670. doi:10.1038/sj.bjp.0706752

  DOI：

  10.1038/sj.bjp.0706752

文献信息

• Detection of multiple H₃ receptor affinity states utilizing [³ H]A-349821, a novel, selective, non-imidazole histamine H₃ receptor inverse agonist radioligand
  作者：David G Witte、Betty Bei Yao、Thomas R Miller、Tracy L Carr、Steven Cassar、Rahul Sharma、Ramin Faghih、Bruce W Surber、Timothy A Esbenshade、Arthur A Hancock、Kathleen M Krueger

  DOI：10.1038/sj.bjp.0706752

  日期：2006.7

  A‐349821 is a selective histamine H3 receptor antagonist/inverse agonist. Herein, binding of the novel non‐imidazole H3 receptor radioligand [3H]A‐349821 to membranes expressing native or recombinant H3 receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N‐α‐methylhistamine ([3H]NαMH). [3H]A‐349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3 receptors with 10‐fold higher affinity compared to rat H3 receptors. [3H]A‐349821 detected larger populations of receptors compared to [3H]NαMH. Displacement of [3H]A‐349821 binding by H3 receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3 receptor agonists was biphasic, suggesting recognition of both high‐ and low‐affinity H3 receptor sites. pKi values of high‐affinity binding sites for H3 receptor competitors utilizing [3H]A‐349821 were highly correlated with pKi values obtained with [3H]NαMH, consistent with labelling of H3 receptors by [3H]A‐349821. Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A‐349821, while displacement of [3H]A‐349821 binding by the H3 receptor agonist histamine was sensitive to GDP. In conclusion, [3H]A‐349821 labels interconvertible high‐ and low‐affinity states of the H3 receptor, and displays improved selectivity over imidazole‐containing H3 receptor antagonist radioligands. [3H]A‐349821 competition studies showed significant differences in the proportions and potencies of high‐ and low‐affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors. British Journal of Pharmacology (2006) 148, 657–670. doi:10.1038/sj.bjp.0706752

  A-349821是一种选择性的组胺H3受体拮抗剂/反激动剂。在此，我们研究并比较了新型非咪唑类H3受体放射配体[3H]A-349821与激动剂[3H]N-α-甲基组胺（[3H]NαMH）在表达内源性或重组H3受体的来自大鼠或人类来源的膜中的结合特性。[3H]A-349821以高亲和力和特异性结合到一个明显的单类的可饱和位点，并且与大鼠H3受体相比，其识别人类H3受体的亲和力高了10倍。[3H]A-349821识别的受体数量比[3H]NαMH多。3H]A-349821结合的被H3受体拮抗剂/反激动剂置换的曲线为单相，提示识别单个结合位点，而H3受体激动剂的置换曲线为双相，提示识别高亲和力和低亲和力的H3受体位点。高亲和力结合位点的H3受体竞争剂的pKi值在使用[3H]A-349821时与使用[3H]NαMH获得的pKi值高度相关，这与[3H]A-349821标记H3受体一致。与使用[3H]NαMH的测定不同，加入GDP对使用[3H]A-349821测定的饱和参数没有影响，而[3H]A-349821结合被H3受体激动剂组胺置换对GDP敏感。结论：[3H]A-349821标记可相互转换的高亲和力和低亲和力的H3受体状态，并且与含有咪唑的H3受体拮抗剂放射配体相比，显示出改进的选择性。[3H]A-349821竞争性结合研究表明，高亲和力和低亲和力位点的比例和效力在不同物种之间存在显著差异，这为H3受体的基本药理性质提供了新信息。英国药理学杂志 (2006) 148, 657–670. doi:10.1038/sj.bjp.0706752