PG01037 | 790658-27-4

• 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: PG01037
• 英文别名: N-[(E)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide
• CAS: 790658-27-4
• 化学式: C₂₆H₂₆Cl₂N₄O
• 分子量: 481.425
• InChiKey: ZMYOIZHRXABMFZ-ONEGZZNKSA-N

物化性质

• 沸点：
  685.3±55.0 °C(Predicted)
• 密度：
  1.253±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  48.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  PG01037 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以32%的产率得到4-(2,3-Dichlorophenyl)-1-(4-(4-(pyridin-2-yl)benzamido)-trans-but-2-enyl)-piperazine 1-oxide
  参考文献：
  名称：

  N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）丁基）芳基羧酰胺的杂环类似物，具有功能化的连接链，作为新的多巴胺D3受体配体：潜在的药物滥用治疗剂。

  摘要：

  多巴胺D3受体拮抗剂和部分激动剂已显示出可卡因和其他滥用药物引起的药物寻找作用。化合物6 [PG01037，（N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）-反式-丁-2-烯基）-4-吡啶-2-基苯甲酰胺）]及相关类似物目前正在对成瘾性动物模型进行评估。在这些研究中，已观察到体外结合亲和力，体内占有率和行为效能之间的差异。这项研究的目的是检查（1）丁基酰胺连接链上的2-吡啶基苯基部分的修饰和（2）与2-芴基酰胺或2-吡啶基苯基酰胺和2-甲氧基系统偶联的丁基酰胺连接链上的羟基，乙酰基和环丙基取代基-或2,3-二氯取代的苯基哌嗪来测量对结合亲和力，D2 / D3选择性的影响，亲脂性和功能。通常，如在竞争结合测定中所测量的，这些修饰在人多巴胺D3（hD3）受体（Ki = 1-5 nM）上具有良好的耐受性。几种类似物对多巴胺D3的选择性比D2和D4受体高100倍以上。此外，尽管所有带有烯烃连接

  DOI：

  10.1021/jm0704200
• 作为产物：
  描述：

  1-(2,3-二氯苯基)哌嗪 在 吡啶 、 碳酸氢钠 、 N,N'-羰基二咪唑 、 肼 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 8.5h， 生成 PG01037
  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

• 4-PHENYLPIPERAZINE DERIVATIVES WITH FUNCTIONALIZED LINKERS AS DOPAMINE D3 RECEPTOR SELECTIVE LIGANDS AND METHODS OF USE
  申请人：Newman Amy Hauck

  公开号：US20100267737A1

  公开（公告）日：2010-10-21

  Dopamine D 3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D 3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at D 3 receptors and achieve high selectivity over D 2 and D 4 receptors.

  多巴胺D3受体拮抗剂和部分激动剂已知能够调节由可卡因和其他滥用物质引起的加强和寻求药物效应。通过在4-苯基哌嗪配体的丁酰胺连接链中引入功能性基团，可以实现改善D3受体亲和力和选择性以及可溶性。披露了一系列连接链衍生物，其中引入了OH或OAc基团等功能性基团。总体而言，这些改性在D3受体中耐受性良好，并实现了对D2和D4受体的高选择性。
• 4-phenylpiperazine derivatives with functionalized linkers as dopamine D3 receptor selective ligands and methods of use
  申请人：Newman Amy Hauck

  公开号：US08748608B2

  公开（公告）日：2014-06-10

  Dopamine D3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at D3 receptors and achieve high selectivity over D2 and D4 receptors.

  多巴胺D3受体拮抗剂和部分激动剂已知能够调节可卡因和其他滥用物质引起的强化和寻药效应。通过在4-苯基哌嗪类配体的丁酰胺连接链中引入功能基团，可以获得改良的D3受体亲和力和选择性，以及水溶性。披露了一系列连接链衍生物，其中引入了OH或OAc基团等功能基团。一般来说，这些修饰在D3受体上很容易耐受，并实现了对D2和D4受体的高选择性。
• 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.
• Heterocyclic Analogues of <i>N</i>-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with Functionalized Linking Chains as Novel Dopamine D3 Receptor Ligands:  Potential Substance Abuse Therapeutic Agents
  作者：Peter Grundt、Katherine M. Prevatt、Jianjing Cao、Michelle Taylor、Christina Z. Floresca、Ji-Kyung Choi、Bruce G. Jenkins、Robert R. Luedtke、Amy Hauck Newman

  DOI：10.1021/jm0704200

  日期：2007.8.1

  Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylben zamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding

  多巴胺D3受体拮抗剂和部分激动剂已显示出可卡因和其他滥用药物引起的药物寻找作用。化合物6 [PG01037，（N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）-反式-丁-2-烯基）-4-吡啶-2-基苯甲酰胺）]及相关类似物目前正在对成瘾性动物模型进行评估。在这些研究中，已观察到体外结合亲和力，体内占有率和行为效能之间的差异。这项研究的目的是检查（1）丁基酰胺连接链上的2-吡啶基苯基部分的修饰和（2）与2-芴基酰胺或2-吡啶基苯基酰胺和2-甲氧基系统偶联的丁基酰胺连接链上的羟基，乙酰基和环丙基取代基-或2,3-二氯取代的苯基哌嗪来测量对结合亲和力，D2 / D3选择性的影响，亲脂性和功能。通常，如在竞争结合测定中所测量的，这些修饰在人多巴胺D3（hD3）受体（Ki = 1-5 nM）上具有良好的耐受性。几种类似物对多巴胺D3的选择性比D2和D4受体高100倍以上。此外，尽管所有带有烯烃连接