MDL 28564

• 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: MDL 28564
• 英文别名: Asp-Ser-Phe-Val-Gly-Leuψ(CH2NH)Leu-NH2；3-Amino-N-[1-(1-{1-[({1-[(1-carbamoyl-3-methyl-butylamino)-methyl]-3-methyl-butylcarbamoyl}-methyl)-carbamoyl]-2-methyl-propylcarbamoyl}-2-phenyl-ethylcarbamoyl)-2-hydroxy-ethyl]-succinamic acid；(3S)-3-amino-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methylpentan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-oxobutanoic acid
• 化学式: C₃₅H₅₈N₈O₉
• 分子量: 734.894
• InChiKey: PWZNYVOVYOCFLQ-CJQGIMJOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  52
• 可旋转键数：
  24
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  284
• 氢给体数：
  10
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  BOC-甘氨酸 、 N-Boc-L-缬氨酸 、 BOC-L-亮氨酸 、 2-甲基-2-丙基[(2S)-4-甲基-1-氧代-2-戊烷基]氨基甲酸酯 、 alkaline earth salt of/the/ methylsulfuric acid 生成 MDL 28564
  参考文献：
  名称：

  A new class of high affinity ligands for the neurokinin A NK2 receptor: .psi.(CH2NR) reduced peptide bond analogs of neurokinin A4-10

  摘要：

  Analogues of [Leu10]NKA4-10 were synthesized in which each of the amide bonds was sequentially replaced with the reduced amide psi(CH2NH) bond to determine the effect of this structural modification on the antagonism of NKA binding to the HUB NK2 receptor. [psi(CH2-NH)9,Leu10]NKA4-10 (6) retained significant affinity for the NK2 receptor (IC50=115 nM) and showed weak partial stimulation of PI turnover (approximately 10-15% of NKA maximum). 6 behaves as a competitive antagonist of NKA-stimulated PI turnover with a pA2=6.7. The secondary amine of the psi(CH2NH) moiety of 6 was converted to a tertiary amine by alkylation. This modification was found to have a small effect upon receptor affinity but did result in attenuation of partial agonist activity. A combination of amino acid substitutions and psi(CH2NH) alkylation yielded [betaAla8,psi(CH2N(CH2)2CH3)9,Phe10]NKA4-10 (21) which has very high affinity for the HUB NK2 receptor. This compound inhibited [I-125]NKA binding with an IC50=1 nM which is equal to the receptor affinity of NKA. Compound 21 also shows very weak partial agonism of PI turnover (less-than-or-equal-to 5% of NKA maximum) which makes this the most potent member of a new class of NKA ligands: psi(CH2NR)9-NKA4-10 analogues which potently antagonize NKA binding and possess minimal partial agonist activity.

  DOI：

  10.1021/jm00099a024

文献信息

• A new class of high affinity ligands for the neurokinin A NK2 receptor: .psi.(CH2NR) reduced peptide bond analogs of neurokinin A4-10
  作者：Scott L. Harbeson、Scott A. Shatzer、Tieu Binh Le、Stephen H. Buck

  DOI：10.1021/jm00099a024

  日期：1992.10

  Analogues of [Leu10]NKA4-10 were synthesized in which each of the amide bonds was sequentially replaced with the reduced amide psi(CH2NH) bond to determine the effect of this structural modification on the antagonism of NKA binding to the HUB NK2 receptor. [psi(CH2-NH)9,Leu10]NKA4-10 (6) retained significant affinity for the NK2 receptor (IC50=115 nM) and showed weak partial stimulation of PI turnover (approximately 10-15% of NKA maximum). 6 behaves as a competitive antagonist of NKA-stimulated PI turnover with a pA2=6.7. The secondary amine of the psi(CH2NH) moiety of 6 was converted to a tertiary amine by alkylation. This modification was found to have a small effect upon receptor affinity but did result in attenuation of partial agonist activity. A combination of amino acid substitutions and psi(CH2NH) alkylation yielded [betaAla8,psi(CH2N(CH2)2CH3)9,Phe10]NKA4-10 (21) which has very high affinity for the HUB NK2 receptor. This compound inhibited [I-125]NKA binding with an IC50=1 nM which is equal to the receptor affinity of NKA. Compound 21 also shows very weak partial agonism of PI turnover (less-than-or-equal-to 5% of NKA maximum) which makes this the most potent member of a new class of NKA ligands: psi(CH2NR)9-NKA4-10 analogues which potently antagonize NKA binding and possess minimal partial agonist activity.