4-((6-(3-chlorobenzylamino)-9-((1S,2R,3S,4R,5S)-3,4-dihydroxy-5-(methylcarbamoyl)bicyclo[3.1.0]hexan-2-yl)-9H-purin-2-yl)ethynyl)benzenesulfonic acid | 1388186-11-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: 4-((6-(3-chlorobenzylamino)-9-((1S,2R,3S,4R,5S)-3,4-dihydroxy-5-(methylcarbamoyl)bicyclo[3.1.0]hexan-2-yl)-9H-purin-2-yl)ethynyl)benzenesulfonic acid
• 英文别名: 4-[2-[6-[(3-chlorophenyl)methylamino]-9-[(1S,2R,3S,4R,5S)-3,4-dihydroxy-5-(methylcarbamoyl)-2-bicyclo[3.1.0]hexanyl]purin-2-yl]ethynyl]benzenesulfonic acid
• CAS: 1388186-11-5
• 化学式: C₂₈H₂₅ClN₆O₆S
• 分子量: 609.062
• InChiKey: VCBOOPKKNOXUFP-WANRRHMFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  42
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  188
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  3-氯苄胺 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 4-((6-(3-chlorobenzylamino)-9-((1S,2R,3S,4R,5S)-3,4-dihydroxy-5-(methylcarbamoyl)bicyclo[3.1.0]hexan-2-yl)-9H-purin-2-yl)ethynyl)benzenesulfonic acid
  参考文献：
  名称：

  Rational Design of Sulfonated A₃Adenosine Receptor-Selective Nucleosides as Pharmacological Tools To Study Chronic Neuropathic Pain

  摘要：

  (N)-Methanocarba(bicyclo[3.1.0]hexane)adenosine derivatives were probed for sites of charged sulfonate substitution, which precludes diffusion across biological membranes, e.g., blood-brain barrier. Molecular modeling predicted that sulfonate groups on C2-phenylethynyl substituents would provide high affinity at both mouse (m) and human (h) A(3) adenosine receptors (ARs), while a N-6-p-sulfophenylethyl substituent would determine higher hA(3)AR vs mA(3)AR affinity. These modeling predictions, based on steric fitting of the binding cavity and crucial interactions with key residues, were confirmed by binding/efficacy studies of synthesized sulfonates. N-6-3-Chlorobenzyl-2-(3-sulfophenylethynyl) derivative 7 (MRS5841) bound selectively to h/m A(3)ARs (K-i(hA(3)AR) = 1.9 nM) as agonist, while corresponding p-sulfo isomer 6 (MRS5701) displayed mixed A(1)/A(3)AR agonism. Both nucleosides administered ip reduced mouse chronic neuropathic pain that was ascribed to either A(3)AR or A(1)/A(3)AR using A(3)AR genetic deletion. Thus, rational design methods based on A(3)AR homology models successfully predicted sites for sulfonate incorporation, for delineating adenosine's CNS vs peripheral actions.

  DOI：

  10.1021/jm4007966

文献信息

• Rational Design of Sulfonated A₃Adenosine Receptor-Selective Nucleosides as Pharmacological Tools To Study Chronic Neuropathic Pain
  作者：Silvia Paoletta、Dilip K. Tosh、Amanda Finley、Elizabeth T. Gizewski、Steven M. Moss、Zhan-Guo Gao、John A. Auchampach、Daniela Salvemini、Kenneth A. Jacobson

  DOI：10.1021/jm4007966

  日期：2013.7.25

  (N)-Methanocarba(bicyclo[3.1.0]hexane)adenosine derivatives were probed for sites of charged sulfonate substitution, which precludes diffusion across biological membranes, e.g., blood-brain barrier. Molecular modeling predicted that sulfonate groups on C2-phenylethynyl substituents would provide high affinity at both mouse (m) and human (h) A(3) adenosine receptors (ARs), while a N-6-p-sulfophenylethyl substituent would determine higher hA(3)AR vs mA(3)AR affinity. These modeling predictions, based on steric fitting of the binding cavity and crucial interactions with key residues, were confirmed by binding/efficacy studies of synthesized sulfonates. N-6-3-Chlorobenzyl-2-(3-sulfophenylethynyl) derivative 7 (MRS5841) bound selectively to h/m A(3)ARs (K-i(hA(3)AR) = 1.9 nM) as agonist, while corresponding p-sulfo isomer 6 (MRS5701) displayed mixed A(1)/A(3)AR agonism. Both nucleosides administered ip reduced mouse chronic neuropathic pain that was ascribed to either A(3)AR or A(1)/A(3)AR using A(3)AR genetic deletion. Thus, rational design methods based on A(3)AR homology models successfully predicted sites for sulfonate incorporation, for delineating adenosine's CNS vs peripheral actions.