pyridine-2-carboxylic acid-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-trans-but-2-enyl}amide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: pyridine-2-carboxylic acid-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-trans-but-2-enyl}amide
• 英文别名: N-[(E)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]pyridine-2-carboxamide
• 化学式: C₂₀H₂₂Cl₂N₄O
• 分子量: 405.327
• InChiKey: IBYDPPHZGREUMK-ONEGZZNKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  48.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-(2,3-二氯苯基)哌嗪 在 碳酸氢钠 、 肼 作用下， 以 乙醇 、 氯仿 、 乙腈 为溶剂， 反应 7.5h， 生成 pyridine-2-carboxylic acid-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-trans-but-2-enyl}amide
  参考文献：
  名称：

  Novel Heterocyclic Trans Olefin Analogues of N-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as Selective Probes with High Affinity for the Dopamine D3 Receptor

  摘要：

  Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological investigations have been hampered by the lack of highly D3 receptor selective compounds that can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist NGB 2904 (1, 9H-fluorene-2-carboxylic acid {4-[(2,3-dichlorophenyl)-piperazin-1-yl]-butyl} amide, K-i (hD3) = 2.0 nM, K-i (hD2(L)) = 112 nM, D2/D3 selectivity ratio of 56) was chosen as a lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D = 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30 novel analogues were synthesized, and their binding affinities were evaluated in competition binding assays in HEK 293 cells transfected with either D2(L), D3, or D4 human dopamine receptors using the high affinity, selective D2-like receptor antagonist I-125-IABN. Structural diversity in the aryl amide end of the molecule Was found to have a major influence on (sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent ligand. Compound 29 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine- 2-yl-benzamide) displayed the most promising pharmacological profile (K-i (hD3) = 0.7 nM, K-i (hD2(L)) = 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells, with an EC50 value of 3.0 nM. Compound 29 was a nearly 5 times more potent antagonist at the D3 receptor than 1 (EC50 = 14.4 nM). Moreover, a decrease in c log D value of similar to2 orders of magnitude was determined for this novel D3-receptor-preferring ligand, compared to 1. In summary, chemical modification of 1 has resulted in compounds with high affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo.

  DOI：

  10.1021/jm049465g

文献信息

• Novel Heterocyclic Trans Olefin Analogues of <i>N</i>-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as Selective Probes with High Affinity for the Dopamine D3 Receptor
  作者：Peter Grundt、Erin E. Carlson、Jianjing Cao、Christina J. Bennett、Elizabeth McElveen、Michelle Taylor、Robert R. Luedtke、Amy Hauck Newman

  DOI：10.1021/jm049465g

  日期：2005.2.1

  Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological investigations have been hampered by the lack of highly D3 receptor selective compounds that can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist NGB 2904 (1, 9H-fluorene-2-carboxylic acid 4-[(2,3-dichlorophenyl)-piperazin-1-yl]-butyl} amide, K-i (hD3) = 2.0 nM, K-i (hD2(L)) = 112 nM, D2/D3 selectivity ratio of 56) was chosen as a lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D = 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30 novel analogues were synthesized, and their binding affinities were evaluated in competition binding assays in HEK 293 cells transfected with either D2(L), D3, or D4 human dopamine receptors using the high affinity, selective D2-like receptor antagonist I-125-IABN. Structural diversity in the aryl amide end of the molecule Was found to have a major influence on (sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent ligand. Compound 29 (N-4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine- 2-yl-benzamide) displayed the most promising pharmacological profile (K-i (hD3) = 0.7 nM, K-i (hD2(L)) = 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells, with an EC50 value of 3.0 nM. Compound 29 was a nearly 5 times more potent antagonist at the D3 receptor than 1 (EC50 = 14.4 nM). Moreover, a decrease in c log D value of similar to2 orders of magnitude was determined for this novel D3-receptor-preferring ligand, compared to 1. In summary, chemical modification of 1 has resulted in compounds with high affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo.