4-tert-butyl-3'-(2-methoxyethoxymethyl)benzhydryl chloride | 219502-62-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-tert-butyl-3'-(2-methoxyethoxymethyl)benzhydryl chloride
• 英文别名: 1-Tert-butyl-4-[chloro-[3-(2-methoxyethoxymethoxy)phenyl]methyl]benzene
• CAS: 219502-62-2
• 化学式: C₂₁H₂₇ClO₃
• 分子量: 362.897
• InChiKey: FTAKTPCSQUKDMZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  27.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-tert-butyl-3'-(2-methoxyethoxymethyl)benzhydryl chloride 在 盐酸 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 乙腈 为溶剂， 反应 26.0h， 生成 (-)-1-(4-tert-butyl-3'-hydroxybenzhydryl)-4-benzylpiperazine
  参考文献：
  名称：

  De Novo Design, Synthesis, and Biological Activities of High-Affinity and Selective Non-Peptide Agonists of the δ-Opioid Receptor

  摘要：

  On the basis of the structure-activity relationships of delta-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained delta-opioid peptide ligand [(2S,3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the delta-opioid receptor over the mu-opioid receptor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000-fold selectivity for the delta-opioid receptor over the delta-opioid receptor. Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the delta-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-C1Phe(4)]DPDPE on the cloned wild-type and mutated human delta-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((alpha R)-alpha(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl] -N,N-diethylbenzamide (SNC-80), another; delta-opioid-selective non-peptide ligand.

  DOI：

  10.1021/jm980374r
• 作为产物：
  描述：

  3-[(2-甲氧基乙氧基)甲氧基]苯甲醛 在 四氯化碳 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成 4-tert-butyl-3'-(2-methoxyethoxymethyl)benzhydryl chloride
  参考文献：
  名称：

  De Novo Design, Synthesis, and Biological Activities of High-Affinity and Selective Non-Peptide Agonists of the δ-Opioid Receptor

  摘要：

  On the basis of the structure-activity relationships of delta-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained delta-opioid peptide ligand [(2S,3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the delta-opioid receptor over the mu-opioid receptor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000-fold selectivity for the delta-opioid receptor over the delta-opioid receptor. Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the delta-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-C1Phe(4)]DPDPE on the cloned wild-type and mutated human delta-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((alpha R)-alpha(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl] -N,N-diethylbenzamide (SNC-80), another; delta-opioid-selective non-peptide ligand.

  DOI：

  10.1021/jm980374r

文献信息

• Exploring the Structure−Activity Relationships of [1-(4-<i>tert</i>-Butyl-3‘-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), A High-Affinity and Selective δ-Opioid Receptor Nonpeptide Agonist Ligand
  作者：Josue Alfaro-Lopez、Toru Okayama、Keiko Hosohata、Peg Davis、Frank Porreca、Henry I. Yamamura、Victor J. Hruby

  DOI：10.1021/jm990337f

  日期：1999.12.1

  SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonist of the delta-opioid receptor. In a previous report we had described the unique biological characteristics of this ligand and also a need for further structural evaluation(6). To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeling studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the original piperazine scaffold (5 and 11). The biological activities of these compounds revealed an important participation of the scaffold in the ligand-receptor interaction. To further explore functional diversity on the scaffold, we have maintained the original piperazine ring and introduced four different functionalities at position 2 of the heterocyclic ring (15a-d; a = CH2-O-CH2-Ph; b = Me; c = CH2Ph; d = CH2OH). The biological activities observed for these compounds showed a very interesting trend in terms of the steric effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the delta-receptor was observed for 15c compared with 15b. This difference may be explained if we postulate that the bioactive conformation of these peptidomimetics is close to the minimal energy conformations calculated in our study. On the basis of these findings we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.
• De Novo Design, Synthesis, and Biological Activities of High-Affinity and Selective Non-Peptide Agonists of the δ-Opioid Receptor
  作者：Subo Liao、Josue Alfaro-Lopez、Mark D. Shenderovich、Keiko Hosohata、Jun Lin、Xiaoping Li、Dagmar Stropova、Peg Davis、Kevin A. Jernigan、Frank Porreca、Henry I. Yamamura、Victor J. Hruby

  DOI：10.1021/jm980374r

  日期：1998.11.1

  On the basis of the structure-activity relationships of delta-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained delta-opioid peptide ligand [(2S,3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the delta-opioid receptor over the mu-opioid receptor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000-fold selectivity for the delta-opioid receptor over the delta-opioid receptor. Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the delta-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-C1Phe(4)]DPDPE on the cloned wild-type and mutated human delta-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((alpha R)-alpha(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl] -N,N-diethylbenzamide (SNC-80), another; delta-opioid-selective non-peptide ligand.