(1S,4R,5R,7S)-(+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicylo-[3.3.1]nonan-7-amine | 455311-42-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1S,4R,5R,7S)-(+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicylo-[3.3.1]nonan-7-amine
• 英文别名: (+)-3-[(1S,4R,5R,7S)-7-amino-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-5-yl]phenol；3-[(1S,4R,5R,7S)-7-amino-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-5-yl]phenol；3-[(1S,4R,5R,7S)-7-amino-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]nonan-5-yl]phenol
• CAS: 455311-42-9
• 化学式: C₂₄H₃₂N₂O
• 分子量: 364.531
• InChiKey: DBPFGWTUHBQYTM-UCIDMZFESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  49.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-苯基环戊烷羧酸 、 (1S,4R,5R,7S)-(+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicylo-[3.3.1]nonan-7-amine 在 TEA 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 作用下， 以 四氢呋喃 为溶剂， 生成 (1SR,4RS,5RS,7SR)-(+/-)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicylo-[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide
  参考文献：
  名称：

  发现首个具有高度有效和选择性阿片类δ受体拮抗剂活性的N-取代的4β-甲基-5-（3-羟基苯基）吗啉。

  摘要：

  已经鉴定出结构上新颖的阿片样物质δ受体选择性拮抗剂。该化合物，（+）-5-（3-羟基苯基）-4-甲基-2-（3-苯基丙基）-2-氮杂双环[3.3.1]非-7-基-（1-苯基-1-环戊烷）羧酰胺[（+）-KF4，（+）-4]在[（35）S] GTPgammaS功能测定中显示0.15 nM的K（e）值。（+）-KF4也是δ反向激动剂，IC（50）值为1.8 nM。据我们所知，这是5-苯基吗啡类阿片类药物中第一个有效的选择性δ阿片受体拮抗剂。

  DOI：

  10.1021/jm030419a
• 作为产物：
  描述：

  (R)-4-(3-异丙氧基苯基)-1,3-二甲基-1,2,3,6-四氢吡啶 在 4-二甲氨基吡啶 、 lithium hydroxide 、 sodium tetrahydroborate 、 正丁基锂 、 草酰氯 、 盐酸羟胺 、 氢溴酸 、 sodium 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 二甲基亚砜 、 三乙胺 、 异丙醇 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 1,2-二氯乙烷 、 甲苯 为溶剂， 反应 72.0h， 生成 (1S,4R,5R,7S)-(+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicylo-[3.3.1]nonan-7-amine
  参考文献：
  名称：

  Discovery of an Opioid κ Receptor Selective Pure Antagonist from a Library of N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphans

  摘要：

  A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4p-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)-7alpha-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identified as the first potent and selective k opioid receptor antagonist from the 5-phenylmorphan class of opioids.

  DOI：

  10.1021/jm020084h

文献信息

• Highly Potent and Selective Phenylmorphan-Based Inverse Agonists of the Opioid δ Receptor
  作者：James B. Thomas、Li Zhang、Hernán A. Navarro、F. Ivy Carroll

  DOI：10.1021/jm060459p

  日期：2006.9.1

  We recently reported the discovery of (+)-5-( 3-hydroxyphenyl)-4-methyl-2-( 3-phenylpropyl)-2-azabicyclo-[ 3.3.1] non-7-yl-( 1-phenyl-1-cyclopentane) carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing potent antagonist activity at the delta opioid receptor. Additional SAR studies involving changes to both the 2-amino and 7-amido N-substituents using this same (+)- morphan scaffold have revealed compounds with improved potency and selectivity for the delta opioid receptor. The highly potent and selective 2,2-dimethylphenylacetamide analogue (+)- N-[( 1S, 4R, 5R, 7S)-5-( 3-hydroxyphenyl)-4-methyl- 2-(3-phenylpropyl)2- azabicyclo[ 3.3.1] non-7-yl]-2-methyl-2-phenylpropanamide ( 13d, delmorphan-A) showed picomolar inhibitory potency ( K-e = 0.1 nM) in the [ S-35] GTP gamma S functional assay with delta opioid receptor selectivity ratios of 103- and 132- fold versus the mu and kappa opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of delta inverse agonist activity within this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the prototypical delta opioid receptor inverse agonist ICI 174 864 ( 22).
• Discovery of an Opioid κ Receptor Selective Pure Antagonist from a Library of N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphans
  作者：James B. Thomas、Robert N. Atkinson、Nivedita Namdev、Richard B. Rothman、Kenneth M. Gigstad、Scott E. Fix、S. Wayne Mascarella、Jason P. Burgess、N. Ariane Vinson、Heng Xu、Christina M. Dersch、Buddy E. Cantrell、Dennis M. Zimmerman、F. Ivy Carroll

  DOI：10.1021/jm020084h

  日期：2002.8.1

  A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4p-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)-7alpha-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identified as the first potent and selective k opioid receptor antagonist from the 5-phenylmorphan class of opioids.
• Discovery of the First N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphan To Possess Highly Potent and Selective Opioid δ Receptor Antagonist Activity
  作者：F. Ivy Carroll、Li Zhang、S. Wayne Mascarella、Hernán A. Navarro、Richard B. Rothman、Buddy E. Cantrell、Dennis M. Zimmerman、James B. Thomas

  DOI：10.1021/jm030419a

  日期：2004.1.1

  A structurally novel opioid delta receptor selective antagonist has been identified. This compound, (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-( 1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-4], showed a K(e) value of 0.15 nM in the [(35)S]GTPgammaS functional assay. (+)-KF4 is also a delta inverse agonist with an IC(50) value of 1.8 nM. To our knowledge, this

  已经鉴定出结构上新颖的阿片样物质δ受体选择性拮抗剂。该化合物，（+）-5-（3-羟基苯基）-4-甲基-2-（3-苯基丙基）-2-氮杂双环[3.3.1]非-7-基-（1-苯基-1-环戊烷）羧酰胺[（+）-KF4，（+）-4]在[（35）S] GTPgammaS功能测定中显示0.15 nM的K（e）值。（+）-KF4也是δ反向激动剂，IC（50）值为1.8 nM。据我们所知，这是5-苯基吗啡类阿片类药物中第一个有效的选择性δ阿片受体拮抗剂。