(S)-N-(4-(4-phenylbenzoylamino)butyl)-N-propyl-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine | 1276031-69-6

• 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)-N-(4-(4-phenylbenzoylamino)butyl)-N-propyl-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine
• 英文别名: 4-phenyl-N-[4-[propyl-[(5S)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl]amino]butyl]benzamide
• CAS: 1276031-69-6
• 化学式: C₂₇H₃₄N₄O
• 分子量: 430.593
• InChiKey: UTFOVXIJDJSMKK-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine 在 三乙酰氧基硼氢化钠 、 sodium cyanoborohydride 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 反应 18.75h， 生成 (R)-N-(4-(4-phenylbenzoylamino)butyl)-N-propyl-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine 、 (S)-N-(4-(4-phenylbenzoylamino)butyl)-N-propyl-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine
  参考文献：
  名称：

  Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D₃ Receptor Binding, Functional Selectivity, and Analysis of Receptor−Ligand Interactions

  摘要：

  Heterocyclic dopamine surrogates of types 5 and 7 were synthesized and investigated for their dopaminergic properties. The enantiomerically pure biphenylcarboxamide (S)-5a displayed an outstanding K-i of 27 pM at the agonist-labeled D-3 receptor and significant selectivity over the D-2 subtype. Measurement of [S-35]GTP gamma S incorporation in the presence of a coexpressed PTX-insensitive G(alpha 0-1) subunit indicated highly efficient G-protein coupling. Comparison of ligand efficacy data from cAMP accumulation and [H-3]thymidine incorporation experiments revealed that ligand biased signaling is exerted by the test compound (S)-5a. Starting from the D-3 crystal structure, a combination of homology modeling and site directed mutagenesis gave valuable insights into the binding mode and the intermolecular origins of stereospecific receptor recognition. According to these data, the superior affinity of the eutomer 5a is caused by the favorable binding energy that results from interaction between the ligand's central ammonium unit and the aspartate residue in position 3.32 of the receptor.

  DOI：

  10.1021/jm101639t

文献信息

• Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D₃ Receptor Binding, Functional Selectivity, and Analysis of Receptor−Ligand Interactions
  作者：Nuska Tschammer、Jan Elsner、Angela Goetz、Katharina Ehrlich、Stefan Schuster、Miriam Ruberg、Julia Kühhorn、Dawn Thompson、Jennifer Whistler、Harald Hübner、Peter Gmeiner

  DOI：10.1021/jm101639t

  日期：2011.4.14

  Heterocyclic dopamine surrogates of types 5 and 7 were synthesized and investigated for their dopaminergic properties. The enantiomerically pure biphenylcarboxamide (S)-5a displayed an outstanding K-i of 27 pM at the agonist-labeled D-3 receptor and significant selectivity over the D-2 subtype. Measurement of [S-35]GTP gamma S incorporation in the presence of a coexpressed PTX-insensitive G(alpha 0-1) subunit indicated highly efficient G-protein coupling. Comparison of ligand efficacy data from cAMP accumulation and [H-3]thymidine incorporation experiments revealed that ligand biased signaling is exerted by the test compound (S)-5a. Starting from the D-3 crystal structure, a combination of homology modeling and site directed mutagenesis gave valuable insights into the binding mode and the intermolecular origins of stereospecific receptor recognition. According to these data, the superior affinity of the eutomer 5a is caused by the favorable binding energy that results from interaction between the ligand's central ammonium unit and the aspartate residue in position 3.32 of the receptor.