O-benzyl-N-Boc-N,2,6-trimethyltyrosine | 194857-87-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: O-benzyl-N-Boc-N,2,6-trimethyltyrosine
• 英文别名: Boc-N-Me-L/D-Dmt(Bzl)-OH；3-(2,6-Dimethyl-4-phenylmethoxyphenyl)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid
• CAS: 194857-87-9
• 化学式: C₂₄H₃₁NO₅
• 分子量: 413.514
• InChiKey: NMGHABDLOSYPBN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  O-benzyl-N-Boc-N,2,6-trimethyltyrosine 在 palladium on activated charcoal TEA 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 TFA*H-N-Me-D-Dmt-Tic-Ala-OH
  参考文献：
  名称：

  Evolution of the Dmt-Tic Pharmacophore:  N-Terminal Methylated Derivatives with Extraordinary δ Opioid Antagonist Activity

  摘要：

  The delta opioid antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary delta receptor binding characteristics [K-i(delta) = 0.022 nM; K-i(u)/K-i(delta) = 150 000] and delta antagonism (pA(2) = 8.2; K-e = 5.7 nM). A change in chirality of Dmt at C alpha (1, 2, 6, 8, 10, 13) curtailed delta receptor parameters, while replacement of its alpha-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with delta receptors. N-Alkylation of H-Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent delta-opioid ligands with high delta receptor binding capabilities and enhanced delta antagonism: (i) N-Me-Dmt-Tic-OH 5 had high delta opioid binding (K-i(delta) = 0.2 nM), elevated delta antagonism on mouse vas deferens (MVD) (pA(2) = 8.5; K-e = 2.8 nM), and nondetectable mu activity with guinea pig ileum (GPI). (ii) N,N-Me-2-Dmt-Tic-OH (12) was equally efficacious in delta receptor binding (K-i(delta) = 0.12 nM; K-i(mu)/K-i(delta) = 20 000), but delta antagonism rose considerably (pA(2) = 9.4; K-e = 0.28 nM) with weak mu antagonism (pA(2) = 5.8; K-e = 1.58 mu M; GPI/MVD = 1:5640). N-Me-(9) and N,N-Me-2-Dmt-Tic-Ala-OH (15) also augmented delta opioid receptor binding, such that 15 demonstrated high affinity (K-i(delta) = 0.0755 nM) and selectivity (K-i(mu)/K-i(delta) = 20 132) with exceptional antagonist activity on MVD (pA(2) = 9.6; K-e = 0.22 nM) and weak antagonism on GPI (pA(2) = 5.8; K-e = 1.58 mu M; GPI/MVD = 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high K-i(delta) (0.31 nM) and excellent antagonist activity (pA(2) = 9.9; K-e = 0.12 nM), the increased activity toward mu receptors in the absence of a free acid function at the C-terminus revealed modest delta selectivity (K-i(mu)/K-i(delta) = 1 655) and somewhat comparable bioactivity (GPI/MVD = 4500). Thus, the data demonstrate that N,N-(Me)(2)-Dmt-Tic-OH (12) and N,N-Me-2-Dmt-Tic-Ala-OH (15) retained high delta receptor affinities and delta selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non-peptide delta antagonists.

  DOI：

  10.1021/jm9607663
• 作为产物：
  描述：

  2-tert-butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid 在 sodium hydroxide 、 sodium hydride 、 potassium carbonate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.75h， 生成 O-benzyl-N-Boc-N,2,6-trimethyltyrosine
  参考文献：
  名称：

  Pitzele; Hamilton; Kudla, Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 888 - 896

  摘要：

  DOI：

文献信息

• Pitzele; Hamilton; Kudla, Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 888 - 896
  作者：Pitzele、Hamilton、Kudla、Tsymbalov、Stapelfeld、Savage、Clare、Hammond、Hansen Jr.

  DOI：——

  日期：——
• Evolution of the Dmt-Tic Pharmacophore:  N-Terminal Methylated Derivatives with Extraordinary δ Opioid Antagonist Activity
  作者：Severo Salvadori、Gianfranco Balboni、Remo Guerrini、Roberto Tomatis、Clementina Bianchi、Sharon D. Bryant、Peter S. Cooper、Lawrence H. Lazarus

  DOI：10.1021/jm9607663

  日期：1997.9.1

  The delta opioid antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary delta receptor binding characteristics [K-i(delta) = 0.022 nM; K-i(u)/K-i(delta) = 150 000] and delta antagonism (pA(2) = 8.2; K-e = 5.7 nM). A change in chirality of Dmt at C alpha (1, 2, 6, 8, 10, 13) curtailed delta receptor parameters, while replacement of its alpha-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with delta receptors. N-Alkylation of H-Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent delta-opioid ligands with high delta receptor binding capabilities and enhanced delta antagonism: (i) N-Me-Dmt-Tic-OH 5 had high delta opioid binding (K-i(delta) = 0.2 nM), elevated delta antagonism on mouse vas deferens (MVD) (pA(2) = 8.5; K-e = 2.8 nM), and nondetectable mu activity with guinea pig ileum (GPI). (ii) N,N-Me-2-Dmt-Tic-OH (12) was equally efficacious in delta receptor binding (K-i(delta) = 0.12 nM; K-i(mu)/K-i(delta) = 20 000), but delta antagonism rose considerably (pA(2) = 9.4; K-e = 0.28 nM) with weak mu antagonism (pA(2) = 5.8; K-e = 1.58 mu M; GPI/MVD = 1:5640). N-Me-(9) and N,N-Me-2-Dmt-Tic-Ala-OH (15) also augmented delta opioid receptor binding, such that 15 demonstrated high affinity (K-i(delta) = 0.0755 nM) and selectivity (K-i(mu)/K-i(delta) = 20 132) with exceptional antagonist activity on MVD (pA(2) = 9.6; K-e = 0.22 nM) and weak antagonism on GPI (pA(2) = 5.8; K-e = 1.58 mu M; GPI/MVD = 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high K-i(delta) (0.31 nM) and excellent antagonist activity (pA(2) = 9.9; K-e = 0.12 nM), the increased activity toward mu receptors in the absence of a free acid function at the C-terminus revealed modest delta selectivity (K-i(mu)/K-i(delta) = 1 655) and somewhat comparable bioactivity (GPI/MVD = 4500). Thus, the data demonstrate that N,N-(Me)(2)-Dmt-Tic-OH (12) and N,N-Me-2-Dmt-Tic-Ala-OH (15) retained high delta receptor affinities and delta selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non-peptide delta antagonists.