4-(4-(2-((7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-quinolin-8-ol | 1214788-12-1

• 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: 4-(4-(2-((7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-quinolin-8-ol
• 英文别名: 4-[4-[2-[[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]-propylamino]ethyl]piperazin-1-yl]quinolin-8-ol
• CAS: 1214788-12-1
• 化学式: C₂₈H₃₆N₄O₂
• 分子量: 460.619
• InChiKey: XNAZWCRZSGGAMO-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  63.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(4-(2-((7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-quinolin-8-ol 在 盐酸 作用下， 以 乙醚 、 乙醇 为溶剂， 以0.05 g的产率得到D-375 hydrochloride
  参考文献：
  名称：

  Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol and Its Analogues as Highly Potent Dopamine D2/D3 Agonists and as Iron Chelator: In Vivo Activity Indicates Potential Application in Symptomatic and Neuroprotective Therapy for Parkinson’s Disease

  摘要：

  The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K-i). Functional activity of selected compounds was carried out with GTP gamma S binding assay. SAR results identified compounds (+)-19a and (-)-19b as two Potent agonists for both D2 and D3 receptors (EC50 (GTP gamma S); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation Studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in Symptomatic and neuroprotective treatment of PD.

  DOI：

  10.1021/jm901618d
• 作为产物：
  描述：

  (+)-7-((2-(4-(8-methoxyquinolin-4-yl)piperazin-1-yl)ethyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-2-ol 在 氢溴酸 、 碳酸氢钠 作用下， 以 水 为溶剂， 生成 4-(4-(2-((7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-quinolin-8-ol
  参考文献：
  名称：

  Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol and Its Analogues as Highly Potent Dopamine D2/D3 Agonists and as Iron Chelator: In Vivo Activity Indicates Potential Application in Symptomatic and Neuroprotective Therapy for Parkinson’s Disease

  摘要：

  The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K-i). Functional activity of selected compounds was carried out with GTP gamma S binding assay. SAR results identified compounds (+)-19a and (-)-19b as two Potent agonists for both D2 and D3 receptors (EC50 (GTP gamma S); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation Studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in Symptomatic and neuroprotective treatment of PD.

  DOI：

  10.1021/jm901618d

文献信息

• Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol and Its Analogues as Highly Potent Dopamine D2/D3 Agonists and as Iron Chelator: In Vivo Activity Indicates Potential Application in Symptomatic and Neuroprotective Therapy for Parkinson’s Disease
  作者：Balaram Ghosh、Tamara Antonio、Maarten E. A. Reith、Aloke K. Dutta

  DOI：10.1021/jm901618d

  日期：2010.3.11

  The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K-i). Functional activity of selected compounds was carried out with GTP gamma S binding assay. SAR results identified compounds (+)-19a and (-)-19b as two Potent agonists for both D2 and D3 receptors (EC50 (GTP gamma S); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation Studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in Symptomatic and neuroprotective treatment of PD.