4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-3-methoxybenzoic acid | 1346263-94-2

• 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-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-3-methoxybenzoic acid
• 英文别名: 4-[3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy]-3-methoxybenzoic acid
• CAS: 1346263-94-2
• 化学式: C₁₇H₂₃N₃O₄
• 分子量: 333.387
• InChiKey: PPFZUFBVEQRFPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  24.0
• 可旋转键数：
  10.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  86.47
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-3-methoxybenzoic acid 在 三氧化硫吡啶 、 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 (S)-4-[3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy]-N-[4-[(6-ethynylcyclohex-3-enyl)propylamino]butyl]-3-methoxybenzamide
  参考文献：
  名称：

  Functionally Selective Dopamine D₂/D₃ Receptor Agonists Comprising an Enyne Moiety

  摘要：

  Dopaminergics of types 1 and 2 incorporating a conjugated enyne as an atypical catechol-simulating moiety were synthesized in enantiomerically pure form and investigated for their metabolic stability. Radioligand binding studies indicated high affinity to D-2-like receptors. The test compounds were evaluated for their ability to differentially activate distinct signaling pathways. Measurement of D-2L- and D-2S-mediated [S-35]GTP gamma S incorporation in the presence of coexpressed G alpha(o) and G alpha(i) subunits showed significantly biased receptor activation for several test compounds. Thus, the 2-azaindolylcarboxamide (S)-2a exhibited substantial functional selectivity for D-2S-promoted G(o) activation over G(i) coupling. The most significant bias was determined for the triazolylalkoxy-substituted benzamide (S)-2c that displayed higher potency for G(o) activation than for G, coupling at the D-2L subtype. Functional selectivity for beta-arrestin recruitment over G(i) activation was observed for the biphenylcarboxamide (R)-1 and the 2-benzothiophenylcarboxamide (S)-2d, whereas the 2-substituted azaindole (S)-2a preferred beta-arrestin recruitment compared to G(o) coupling.

  DOI：

  10.1021/jm400520c
• 作为产物：
  描述：

  methyl 4-[3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy]-3-methoxybenzoate 在 potassium hydroxide 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以97%的产率得到4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-3-methoxybenzoic acid
  参考文献：
  名称：

  Development of a Bivalent Dopamine D₂ Receptor Agonist

  摘要：

  Bivalent D-2 agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D-2 receptor antagonists of type 1, the bivalent agonist 2 was synthesized when a spacer built from 22 atoms was employed. Compared to the monovalent control compound 6 containing a capped spacer, the bis-aminoindane derivative 2 revealed substantial steepening of the competition curve, indicating a bivalent binding mode. Dimer-specific Hill slopes were not a result of varying functional properties because both the dopaminergic 2 and the monovalent control agent 6 proved to be D-2 agonists substantially inhibiting cAMP accumulation and inducing D-2 receptor internalization. Investigation of the heterobivalent ligands 8 and 9, containing an agonist and a phenylpiperazine-based antagonist pharmacophore, revealed moderate steepening of the displacement curves and antagonist to very weak partial agonist properties.

  DOI：

  10.1021/jm2009919

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.