(S)-2-chloro-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide | 1003565-81-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: (S)-2-chloro-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide
• 英文别名: (-)-2-chloro-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide；2-chloro-N-[(2S)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl]-N-propylacetamide
• CAS: 1003565-81-8
• 化学式: C₁₆H₂₂ClNO₂
• 分子量: 295.809
• InChiKey: MCCHTHBEBRGCNE-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (S)-2-chloro-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide 在 lithium aluminium tetrahydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 6.0h， 生成 N¹,N²-bis((S)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N¹,N²-dipropylethane-1,2-diamine
  参考文献：
  名称：

  Novel Bivalent Ligands for D2/D3 Dopamine Receptors: Significant Cooperative Gain in D2 Affinity and Potency

  摘要：

  This report describes development of a series of novel bivalent molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT. The spacer length in the bivalent compounds had a pronounced influence on affinity for D2 receptors. A 23-fold increase of D2 affinity was observed at a spacer length of 9 or 10 (compounds lid and 14b) as compared to monovalent 5-OH-DPAT (K-ij 2.5 and 2.0 vs 59 nM for 11d and 146 vs 5-OH-DPAT, respectively). The functional potency of 11d and 14b indicated a 24- and 94-fold increase in potency at the D2 receptor as compared to 5-OH-DPAT (EC50; 1.7 and 0.44 vs 41 nM for 11d and 14b vs 5-OH-DPAT, respectively). These are the most potent bivalent agonists for the D2 receptor known to date. This synergism is consonant with cooperative interaction at the two orthosteric binding sites in the homodimeric receptor.

  DOI：

  10.1021/ml3002117
• 作为产物：
  描述：

  (S)-1,2,3,4-四氢-5-甲氧基-N-丙基-2-萘胺盐酸盐 、 氯乙酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以94%的产率得到(S)-2-chloro-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide
  参考文献：
  名称：

  Further delineation of hydrophobic binding sites in dopamine D2/D3 receptors for N-4 substituents on the piperazine ring of the hybrid template 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol

  摘要：

  Here we report a structure-activity relationship (SAR) study of analogues of 5/7-{[2-(4-aryl-piperazin-1-yl)- ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our SAR is focused on introduction of various substitutions in the piperazine ring of the hybrid template. The goal behind this study is to delineate the nature of the binding pocket for N-aryl substitution in the piperazine ring by observing the effect of various hydrophobic and other heteroaromatic substitutions on binding affinity (K-i), as measured with tritiated spiperone and HEK-293 cells expressing either D-2 or D-3 receptors. Functional activity of selected compounds was assessed with the GTP gamma S binding assay. Compound 8d was the most selective for the D-3 receptor in the spiperone binding assay. An interesting similarity in binding affinity was observed between isoquinoline derivative D-301 and the 2-substituted pyridine derivative 8d, suggesting the importance of relative spatial relationships between the N-atom of the ligand and the molecular determinants of the binding pocket in D-2/D-3 receptors. Functional activity assays demonstrated high potency and selectivity of (+)-8a and (-)-28b (D-2/D-3 (ratio of EC50): 105 and 202, respectively) for the D-3 receptor and both compounds were more selective compared to the reference drug ropinirole (D-2/D-3 (ratio of EC50): 29.5). (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.025

文献信息

• Development of (<i>S</i>)-<i>N</i>⁶-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-<i>N</i>⁶-propyl-4,5,6,7-tetrahydrobenzo[<i>d</i>]-thiazole-2,6-diamine and Its Analogue as a D3 Receptor Preferring Agonist: Potent in Vivo Activity in Parkinson’s Disease Animal Models
  作者：Balaram Ghosh、Tamara Antonio、Juan Zhen、Prashant Kharkar、Maarten E. A. Reith、Aloke K. Dutta

  DOI：10.1021/jm901184n

  日期：2010.2.11

  Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out, Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K-i). Functional activity of selected compounds in stimulating GTP gamma S binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (-)-24c (D301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC50 (GTP gamma S); D3 = 0.52 nM; D2/D3 (EC50): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity. The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson's disease (PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.
• Further delineation of hydrophobic binding sites in dopamine D2/D3 receptors for N-4 substituents on the piperazine ring of the hybrid template 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol
  作者：Balaram Ghosh、Tamara Antonio、Bhaskar Gopishetty、Maarten Reith、Aloke Dutta

  DOI：10.1016/j.bmc.2010.06.025

  日期：2010.8

  Here we report a structure-activity relationship (SAR) study of analogues of 5/7-[2-(4-aryl-piperazin-1-yl)- ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our SAR is focused on introduction of various substitutions in the piperazine ring of the hybrid template. The goal behind this study is to delineate the nature of the binding pocket for N-aryl substitution in the piperazine ring by observing the effect of various hydrophobic and other heteroaromatic substitutions on binding affinity (K-i), as measured with tritiated spiperone and HEK-293 cells expressing either D-2 or D-3 receptors. Functional activity of selected compounds was assessed with the GTP gamma S binding assay. Compound 8d was the most selective for the D-3 receptor in the spiperone binding assay. An interesting similarity in binding affinity was observed between isoquinoline derivative D-301 and the 2-substituted pyridine derivative 8d, suggesting the importance of relative spatial relationships between the N-atom of the ligand and the molecular determinants of the binding pocket in D-2/D-3 receptors. Functional activity assays demonstrated high potency and selectivity of (+)-8a and (-)-28b (D-2/D-3 (ratio of EC50): 105 and 202, respectively) for the D-3 receptor and both compounds were more selective compared to the reference drug ropinirole (D-2/D-3 (ratio of EC50): 29.5). (C) 2010 Elsevier Ltd. All rights reserved.
• Novel Bivalent Ligands for D2/D3 Dopamine Receptors: Significant Cooperative Gain in D2 Affinity and Potency
  作者：Sanjib Gogoi、Swati Biswas、Gyan Modi、Tamara Antonio、Maarten E. A. Reith、Aloke K. Dutta

  DOI：10.1021/ml3002117

  日期：2012.12.13

  This report describes development of a series of novel bivalent molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT. The spacer length in the bivalent compounds had a pronounced influence on affinity for D2 receptors. A 23-fold increase of D2 affinity was observed at a spacer length of 9 or 10 (compounds lid and 14b) as compared to monovalent 5-OH-DPAT (K-ij 2.5 and 2.0 vs 59 nM for 11d and 146 vs 5-OH-DPAT, respectively). The functional potency of 11d and 14b indicated a 24- and 94-fold increase in potency at the D2 receptor as compared to 5-OH-DPAT (EC50; 1.7 and 0.44 vs 41 nM for 11d and 14b vs 5-OH-DPAT, respectively). These are the most potent bivalent agonists for the D2 receptor known to date. This synergism is consonant with cooperative interaction at the two orthosteric binding sites in the homodimeric receptor.