3,6-bis[(Nα-Boc-Tyr)aminomethyl]-5-methyl-2(1H)-pyrazinone | 627535-23-3

• 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: 3,6-bis[(Nα-Boc-Tyr)aminomethyl]-5-methyl-2(1H)-pyrazinone
• 英文别名: 3,6-bis[(N^α-Boc-Tyr)aminomethyl]-5-methyl-2(1H)-pyrazinone
• CAS: 627535-23-3
• 化学式: C₃₅H₄₆N₆O₉
• 分子量: 694.785
• InChiKey: KHXXHGJGCXWSJS-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.99
• 重原子数：
  50.0
• 可旋转键数：
  12.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  221.07
• 氢给体数：
  7.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  3,6-bis[(Nα-Boc-Tyr)aminomethyl]-5-methyl-2(1H)-pyrazinone 在 苯甲醚 、 三氟乙酸 作用下， 反应 1.0h， 生成 3,6-bis(Tyr-aminomethyl)-5-methyl-2(1H)-pyrazinone
  参考文献：
  名称：

  Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH₂)_n]-2(1H)-pyrazinone with Central-Mediated Analgesia

  摘要：

  The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.

  DOI：

  10.1021/jm0304616
• 作为产物：
  描述：

  3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one 在 N-甲基吗啉 、 氢溴酸 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 3,6-bis[(Nα-Boc-Tyr)aminomethyl]-5-methyl-2(1H)-pyrazinone
  参考文献：
  名称：

  Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH₂)_n]-2(1H)-pyrazinone with Central-Mediated Analgesia

  摘要：

  The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.

  DOI：

  10.1021/jm0304616