(S)-4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-N-(4-((6-ethynyl-3,4-dihydro-2H-pyran-3-yl)propylamino)butyl)-3-methoxybenzamide

• 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: (S)-4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-N-(4-((6-ethynyl-3,4-dihydro-2H-pyran-3-yl)propylamino)butyl)-3-methoxybenzamide
• 英文别名: 4-[3-(1-butyltriazol-4-yl)propoxy]-N-[4-[[(3S)-6-ethynyl-3,4-dihydro-2H-pyran-3-yl]-propylamino]butyl]-3-methoxybenzamide
• 化学式: C₃₁H₄₅N₅O₄
• 分子量: 551.729
• InChiKey: XPMUUENUQYZASR-MHZLTWQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  40
• 可旋转键数：
  19
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  90.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  L-谷氨酰胺 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium tetrahydroborate 、 copper(l) iodide 、 lithium aluminium tetrahydride 、 N,N-二甲基乙醇胺 、 palladium 10% on activated carbon 、 四丁基氟化铵 、 氢气 、 双(三甲基硅烷基)氨基钾 、 三乙酰氧基硼氢化钠 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 148.0h， 生成 (S)-4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-N-(4-((6-ethynyl-3,4-dihydro-2H-pyran-3-yl)propylamino)butyl)-3-methoxybenzamide
  参考文献：
  名称：

  Molecular Determinants of Biased Agonism at the Dopamine D₂Receptor

  摘要：

  The development of biased (functionally selective) ligands Provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D-2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline-derived agonists on functional selectivity at D-2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial beta-arrestin recruitment.

  DOI：

  10.1021/jm501889t

文献信息

• Molecular Determinants of Biased Agonism at the Dopamine D₂Receptor
  作者：Dietmar Weichert、Ashutosh Banerjee、Christine Hiller、Ralf C. Kling、Harald Hübner、Peter Gmeiner

  DOI：10.1021/jm501889t

  日期：2015.3.26

  The development of biased (functionally selective) ligands Provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D-2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline-derived agonists on functional selectivity at D-2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial beta-arrestin recruitment.