N-(trans-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indene-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: N-(trans-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indene-2-carboxamide
• 化学式: C₂₈H₃₁N₃O
• 分子量: 425.574
• InChiKey: BMSRAVZGDWSPNK-DXKIZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.62
• 重原子数：
  32.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  56.13
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  (trans-4-Aminocyclohexyl)acetic acid 在 盐酸 、 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 三乙酰氧基硼氢化钠 、 二异丁基氢化铝 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 36.5h， 生成 N-(trans-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indene-2-carboxamide
  参考文献：
  名称：

  Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D₂ Receptor

  摘要：

  We recently demonstrated that 5B269652 (1) engages one protomer of a dopamine D-2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric "head" groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R "privileged structures" generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.

  DOI：

  10.1021/acs.jmedchem.5b00581

文献信息

• Structure–Activity Study of <i>N</i>-((<i>trans</i>)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1<i>H</i>)-yl)ethyl)cyclohexyl)-1<i>H</i>-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D₂ Receptor
  作者：Jeremy Shonberg、Christopher Draper-Joyce、Shailesh N. Mistry、Arthur Christopoulos、Peter J. Scammells、J. Robert Lane、Ben Capuano

  DOI：10.1021/acs.jmedchem.5b00581

  日期：2015.7.9

  We recently demonstrated that 5B269652 (1) engages one protomer of a dopamine D-2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric "head" groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R "privileged structures" generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.