1,4-dihydrotrigonellyl-Ala-Ala-Gln-Leu-Pro-Gly-OCho

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 1,4-dihydrotrigonellyl-Ala-Ala-Gln-Leu-Pro-Gly-OCho
• 英文别名: [(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] 2-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[(1-methyl-4H-pyridine-3-carbonyl)amino]propanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]acetate
• 化学式: C₅₈H₉₂N₈O₉
• 分子量: 1045.42
• InChiKey: BWWQMQGWTIVQPZ-AOXWHNQASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  75
• 可旋转键数：
  24
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  238
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  trigonellyl-Ala-Ala-Gln-Leu-Pro-Gly-OCho monoethyl sulfate 在 sodium dithionite 、 碳酸氢钠 作用下， 以 甲醇 为溶剂， 反应 0.67h， 以34%的产率得到1,4-dihydrotrigonellyl-Ala-Ala-Gln-Leu-Pro-Gly-OCho
  参考文献：
  名称：

  Metabolism-Based Brain-Targeting System for a Thyrotropin-Releasing Hormone Analogue

  摘要：

  Gln-Leu-Pro-Gly, a progenitor sequence for the thyrotropin-releasing hormone (TRH) analogue [Leu(2)]TRH (pGlu-Leu-Pro-NH2), was covalently and bioreversibly modified on its N- and C-termini (by a 1,4-dihydrotrigonellyl and a cholesteryl group, respectively) to create lipoidal brain-targeting systems for the TRH analogue. The mechanism of targeting and the recovery of the parent peptide at the target site involve several enzymatic steps, including the oxidation of the 1,4-dihydropyridine moiety. Due to the lipid insolublity of the peptide pyridinium conjugate obtained after this reaction, one of the rudimentary steps of brain targeting (i.e., trapping in the central nervous system) can be accomplished. Our design also included spacer amino acid(s) inserted between the N-terminal residue of the progenitor sequence and the dihydrotrigonellyl group to facilitate the posttargeting removal of the attached modification. The release of the TRH analogue in the brain is orchestrated by a sequential metabolism utilizing esterase/lipase, peptidyl glycine alpha-amidating monooxygenase (PAM), peptidase cleavage, and glutaminyl cyclase. In addition to in vitro experiments to prove the designed mechanism of action, the efficacy of brain targeting for [Leu(2)]TRH administered in the form of chemical-targeting systems containing the embedded progenitor sequence was monitored by the antagonistic effect of the peptide on the barbiturate-induced anesthesia (measure of the activational effect on cholinergic neurons) in mice, and considerable improvement was achieved over the efficacy of the parent peptide upon casing this paradigm.

  DOI：

  10.1021/jm980526i

文献信息

• Metabolism-Based Brain-Targeting System for a Thyrotropin-Releasing Hormone Analogue
  作者：Laszlo Prokai、Katalin Prokai-Tatrai、Xudong Ouyang、Ho-Seung Kim、Whei-Mei Wu、Alevtina Zharikova、Nicholas Bodor

  DOI：10.1021/jm980526i

  日期：1999.11.1

  Gln-Leu-Pro-Gly, a progenitor sequence for the thyrotropin-releasing hormone (TRH) analogue [Leu(2)]TRH (pGlu-Leu-Pro-NH2), was covalently and bioreversibly modified on its N- and C-termini (by a 1,4-dihydrotrigonellyl and a cholesteryl group, respectively) to create lipoidal brain-targeting systems for the TRH analogue. The mechanism of targeting and the recovery of the parent peptide at the target site involve several enzymatic steps, including the oxidation of the 1,4-dihydropyridine moiety. Due to the lipid insolublity of the peptide pyridinium conjugate obtained after this reaction, one of the rudimentary steps of brain targeting (i.e., trapping in the central nervous system) can be accomplished. Our design also included spacer amino acid(s) inserted between the N-terminal residue of the progenitor sequence and the dihydrotrigonellyl group to facilitate the posttargeting removal of the attached modification. The release of the TRH analogue in the brain is orchestrated by a sequential metabolism utilizing esterase/lipase, peptidyl glycine alpha-amidating monooxygenase (PAM), peptidase cleavage, and glutaminyl cyclase. In addition to in vitro experiments to prove the designed mechanism of action, the efficacy of brain targeting for [Leu(2)]TRH administered in the form of chemical-targeting systems containing the embedded progenitor sequence was monitored by the antagonistic effect of the peptide on the barbiturate-induced anesthesia (measure of the activational effect on cholinergic neurons) in mice, and considerable improvement was achieved over the efficacy of the parent peptide upon casing this paradigm.