(R,S)-4-methyloxycarbonylamino-4-methyl-1,2,4,5- tetrahydro-2-benzazepin-3-one | 1142954-17-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: (R,S)-4-methyloxycarbonylamino-4-methyl-1,2,4,5- tetrahydro-2-benzazepin-3-one
• 英文别名: (R,S)-4-methyloxycarbonylamino-4-methyl-1,2,4,5-tetrahydro-2-benzazepin-3-one
• CAS: 1142954-17-3
• 化学式: C₁₃H₁₆N₂O₃
• 分子量: 248.282
• InChiKey: FTMKAWGRXVOYCL-UHFFFAOYSA-N

物化性质

• 熔点：
  231.4-233.2 °C
• 沸点：
  485.1±45.0 °C(predicted)
• 密度：
  1.22±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.97
• 重原子数：
  18.0
• 可旋转键数：
  1.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  67.43
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (R,S)-4-methyloxycarbonylamino-4-methyl-1,2,4,5- tetrahydro-2-benzazepin-3-one 在 氢溴酸 、 sodium hydride 、 溶剂黄146 作用下， 生成 2-(4-amino-4-methyl-3-oxo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)acetic acid
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Automated Docking of Constrained Analogues of the Opioid Peptide H-Dmt-d-Ala-Phe-Gly-NH₂ Using the 4- or 5-Methyl Substituted 4-Amino-1,2,4,5-tetrahydro-2-benzazepin-3-one Scaffold

  摘要：

  The Phe(3) residue of the N-terminal tetrapeptide of dermorphin (H-Dmt-D-Ala-Phe-Gly-NH2) was conformationally constrained using 4- or 5-methyl-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) stereoisomeric scaffolds. Several of the synthesized peptides were determined to be high affinity agonists for the mu opioid receptor (OPRM) with selectivity over the delta opioid receptor (OPRD). Interesting effects of the Aba configuration on ligand binding affinity were observed. H-Dmt-D-Ala-erythro-(4S,5S)-5-Me-Aba-Gly-NH2 9 and H-Dmt-threo-(4R,5S)-5-Me-Aba-Gly-NH2 12 exhibited subnanomolar affinity for OPRM, while they possess an opposite absolute configuration at position 4 of the Aba ring. However, in the 4-methyl substituted analogues, H-Dmt-D-Ala-(4R)-Me-Aba-Gly-NH2 14 was significantly more potent than the (4S)-derivative 13. These unexpected results were rationalized using the binding poses predicted by molecular docking simulations. Interestingly, H-Dmt-D-Ala-(4R)-Me-Aba-Gly-NH2 14 is proposed to bind in a different mode compared with the other analogues. Moreover, in contrast to Ac-4-Me-Aba-NH-Me, which adopts a beta-turn in solution and in the crystal structure, the binding mode of this analogue suggests an alternative receptor-bound conformation.

  DOI：

  10.1021/jm2003574
• 作为产物：
  描述：

  (RS)-3-(2-(aminomethyl)phenyl)-2-(methoxycarbonylamino)-2-methylpropanoic acid 在 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 生成 (R,S)-4-methyloxycarbonylamino-4-methyl-1,2,4,5- tetrahydro-2-benzazepin-3-one
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Automated Docking of Constrained Analogues of the Opioid Peptide H-Dmt-d-Ala-Phe-Gly-NH₂ Using the 4- or 5-Methyl Substituted 4-Amino-1,2,4,5-tetrahydro-2-benzazepin-3-one Scaffold

  摘要：

  The Phe(3) residue of the N-terminal tetrapeptide of dermorphin (H-Dmt-D-Ala-Phe-Gly-NH2) was conformationally constrained using 4- or 5-methyl-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) stereoisomeric scaffolds. Several of the synthesized peptides were determined to be high affinity agonists for the mu opioid receptor (OPRM) with selectivity over the delta opioid receptor (OPRD). Interesting effects of the Aba configuration on ligand binding affinity were observed. H-Dmt-D-Ala-erythro-(4S,5S)-5-Me-Aba-Gly-NH2 9 and H-Dmt-threo-(4R,5S)-5-Me-Aba-Gly-NH2 12 exhibited subnanomolar affinity for OPRM, while they possess an opposite absolute configuration at position 4 of the Aba ring. However, in the 4-methyl substituted analogues, H-Dmt-D-Ala-(4R)-Me-Aba-Gly-NH2 14 was significantly more potent than the (4S)-derivative 13. These unexpected results were rationalized using the binding poses predicted by molecular docking simulations. Interestingly, H-Dmt-D-Ala-(4R)-Me-Aba-Gly-NH2 14 is proposed to bind in a different mode compared with the other analogues. Moreover, in contrast to Ac-4-Me-Aba-NH-Me, which adopts a beta-turn in solution and in the crystal structure, the binding mode of this analogue suggests an alternative receptor-bound conformation.

  DOI：

  10.1021/jm2003574

文献信息

• Influence of ring substitution on the conformation and β-turn mimicry of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one peptide mimetics
  作者：Rien De Wachter、Luc Brans、Steven Ballet、Isabelle Van den Eynde、Debby Feytens、Attila Keresztes、Geza Toth、Zofia Urbanczyk-Lipkowska、Dirk Tourwé

  DOI：10.1016/j.tet.2009.01.057

  日期：2009.3

  Analogs of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-ones, containing a methyl substituent at the 4- or 5-position, or a phenyl substituent at C-1, were prepared. Conformational analysis of tetrapeptide models containing these analogs indicated different conformations of the benzazepinone ring, and extended backbone conformations, except for the 4-methyl-substituted analog. The latter was shown to have a strong preference for a turn conformation. Incorporation into the N-terminal tetrapeptide sequence of dermorphin resulted in potent opioid analogs and an indication that the receptor-bound conformation might not adopt a turn structure. (C) 2009 Elsevier Ltd. All rights reserved.