3-{[6-({8-[(6-aminohexyl)amino]octyl}amino)hexyl]amino}propanenitrile | 253877-97-3

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-{[6-({8-[(6-aminohexyl)amino]octyl}amino)hexyl]amino}propanenitrile
• 英文别名: 3-[6-[8-(6-Aminohexylamino)octylamino]hexylamino]propanenitrile
• CAS: 253877-97-3
• 化学式: C₂₃H₄₉N₅
• 分子量: 395.676
• InChiKey: XVSVGERLILYLGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  28
• 可旋转键数：
  24
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  85.9
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-{[6-({8-[(6-aminohexyl)amino]octyl}amino)hexyl]amino}propanenitrile 在 sodium tetrahydroborate 、 3 A molecular sieve 作用下， 以 乙醇 为溶剂， 反应 0.5h， 生成 3-[(6-{[8-({6-[(2-methoxybenzyl)amino]hexyl}amino)octyl]amino}hexyl)amino]propanenitrile
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Symmetrically and Unsymmetrically Substituted Methoctramine-Related Polyamines as Muscular Nicotinic Receptor Noncompetitive Antagonists

  摘要：

  The universal template approach to drug design foresees that a polyamine can be modified in such a way to recognize any neurotransmitter receptor. Thus, hybrids of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine (1) and PhTX-343 (2), respectively, were synthesized to produce novel inhibitors of muscular nicotinic acetylcholine receptors. Polyamines 3-25 were synthesized and their biological profiles were evaluated at frog rectus abdominis muscle nicotinic receptors and guinea pig left atria (M-2) and ileum longitudinal muscle (M-3) muscarinic acetylcholine receptors. All of the compounds, like prototypes 1 and 2, were noncompetitive antagonists of nicotinic receptors while being, like 1, competitive antagonists at,muscarinic M-2 and M-3 receptor subtypes. interestingly, polyamines bearing a low number of methylenes between the nitrogen atoms, as in 3, 6, and 7, displayed a biological profile similar to that of 2: a noncompetitive antagonism at nicotinic receptors in the 7-25 mu M range while not showing any antagonism for muscarinic receptors up to 10 mu M. increasing the number of methylenes separating these nitrogen atoms in methoctramine related tetraamines resulted in a significant improvement; in potency at nicotinic receptors. The most potent tetraamine was 19, bearing a 12 methylene spacer between the nitrogen atoms, which was 12-fold and 250-fold more potent than prototypes 1 and 2, respectively. Tetraamines 9-11, bearing a rather rigid spacer between the nitrogen atoms instead of the very flexible polymethylene chain, displayed a profile similar to that of 1 at nicotinic receptors, whereas a significant decrease in potency was observed at muscarinic M-2 receptors. This finding may have relevance in understanding the mode of interaction with these receptors. Similarly, the constrained analogue 12 of methoctramine showed a decrease in potency at nicotinic and muscarinic M-2 receptors, revealing that the tricyclic system, which incorporates the 2-methoxybenzylamine moiety of 1, does not represent a good pharmacophore for activity at these sites. A most intriguing finding was the observation that the photolabile tetraamine 22 was more potent than methoctramine at nicotinic receptors and, what is more important, it inhibited a closed stale of the receptor.

  DOI：

  10.1021/jm991110n
• 作为产物：
  描述：

  N,N'-bis(6-aminohexyl)-1,8-octanediamine 、 丙烯腈 以 甲醇 为溶剂， 反应 8.0h， 生成 3-{[6-({8-[(6-aminohexyl)amino]octyl}amino)hexyl]amino}propanenitrile 、 3-{[6-({8-[(6-aminohexyl)amino]octyl}amino)hexyl]amino}propanenitrile
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Symmetrically and Unsymmetrically Substituted Methoctramine-Related Polyamines as Muscular Nicotinic Receptor Noncompetitive Antagonists

  摘要：

  The universal template approach to drug design foresees that a polyamine can be modified in such a way to recognize any neurotransmitter receptor. Thus, hybrids of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine (1) and PhTX-343 (2), respectively, were synthesized to produce novel inhibitors of muscular nicotinic acetylcholine receptors. Polyamines 3-25 were synthesized and their biological profiles were evaluated at frog rectus abdominis muscle nicotinic receptors and guinea pig left atria (M-2) and ileum longitudinal muscle (M-3) muscarinic acetylcholine receptors. All of the compounds, like prototypes 1 and 2, were noncompetitive antagonists of nicotinic receptors while being, like 1, competitive antagonists at,muscarinic M-2 and M-3 receptor subtypes. interestingly, polyamines bearing a low number of methylenes between the nitrogen atoms, as in 3, 6, and 7, displayed a biological profile similar to that of 2: a noncompetitive antagonism at nicotinic receptors in the 7-25 mu M range while not showing any antagonism for muscarinic receptors up to 10 mu M. increasing the number of methylenes separating these nitrogen atoms in methoctramine related tetraamines resulted in a significant improvement; in potency at nicotinic receptors. The most potent tetraamine was 19, bearing a 12 methylene spacer between the nitrogen atoms, which was 12-fold and 250-fold more potent than prototypes 1 and 2, respectively. Tetraamines 9-11, bearing a rather rigid spacer between the nitrogen atoms instead of the very flexible polymethylene chain, displayed a profile similar to that of 1 at nicotinic receptors, whereas a significant decrease in potency was observed at muscarinic M-2 receptors. This finding may have relevance in understanding the mode of interaction with these receptors. Similarly, the constrained analogue 12 of methoctramine showed a decrease in potency at nicotinic and muscarinic M-2 receptors, revealing that the tricyclic system, which incorporates the 2-methoxybenzylamine moiety of 1, does not represent a good pharmacophore for activity at these sites. A most intriguing finding was the observation that the photolabile tetraamine 22 was more potent than methoctramine at nicotinic receptors and, what is more important, it inhibited a closed stale of the receptor.

  DOI：

  10.1021/jm991110n

文献信息

• Design, Synthesis, and Biological Evaluation of Symmetrically and Unsymmetrically Substituted Methoctramine-Related Polyamines as Muscular Nicotinic Receptor Noncompetitive Antagonists
  作者：Michela Rosini、Roberta Budriesi、M. Gabriele Bixel、Maria L. Bolognesi、Alberto Chiarini、Ferdinand Hucho、Povl Krogsgaard-Larsen、Ian R. Mellor、Anna Minarini、Vincenzo Tumiatti、Peter N. R. Usherwood、Carlo Melchiorre

  DOI：10.1021/jm991110n

  日期：1999.12.1

  The universal template approach to drug design foresees that a polyamine can be modified in such a way to recognize any neurotransmitter receptor. Thus, hybrids of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine (1) and PhTX-343 (2), respectively, were synthesized to produce novel inhibitors of muscular nicotinic acetylcholine receptors. Polyamines 3-25 were synthesized and their biological profiles were evaluated at frog rectus abdominis muscle nicotinic receptors and guinea pig left atria (M-2) and ileum longitudinal muscle (M-3) muscarinic acetylcholine receptors. All of the compounds, like prototypes 1 and 2, were noncompetitive antagonists of nicotinic receptors while being, like 1, competitive antagonists at,muscarinic M-2 and M-3 receptor subtypes. interestingly, polyamines bearing a low number of methylenes between the nitrogen atoms, as in 3, 6, and 7, displayed a biological profile similar to that of 2: a noncompetitive antagonism at nicotinic receptors in the 7-25 mu M range while not showing any antagonism for muscarinic receptors up to 10 mu M. increasing the number of methylenes separating these nitrogen atoms in methoctramine related tetraamines resulted in a significant improvement; in potency at nicotinic receptors. The most potent tetraamine was 19, bearing a 12 methylene spacer between the nitrogen atoms, which was 12-fold and 250-fold more potent than prototypes 1 and 2, respectively. Tetraamines 9-11, bearing a rather rigid spacer between the nitrogen atoms instead of the very flexible polymethylene chain, displayed a profile similar to that of 1 at nicotinic receptors, whereas a significant decrease in potency was observed at muscarinic M-2 receptors. This finding may have relevance in understanding the mode of interaction with these receptors. Similarly, the constrained analogue 12 of methoctramine showed a decrease in potency at nicotinic and muscarinic M-2 receptors, revealing that the tricyclic system, which incorporates the 2-methoxybenzylamine moiety of 1, does not represent a good pharmacophore for activity at these sites. A most intriguing finding was the observation that the photolabile tetraamine 22 was more potent than methoctramine at nicotinic receptors and, what is more important, it inhibited a closed stale of the receptor.