14β-amino-5β-methyl-7,8-dihydro-N-(cyclopropylmethyl)norcodeinone | 152660-77-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: 14β-amino-5β-methyl-7,8-dihydro-N-(cyclopropylmethyl)norcodeinone
• CAS: 152660-77-0
• 化学式: C₂₂H₂₈N₂O₃
• 分子量: 368.476
• InChiKey: KYUSVNILJIJILO-YPVJZLTNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.18
• 重原子数：
  27.0
• 可旋转键数：
  3.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  64.79
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  3-(4-硝基苯基)丙酰氯 、 14β-amino-5β-methyl-7,8-dihydro-N-(cyclopropylmethyl)norcodeinone 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以60 mg的产率得到
  参考文献：
  名称：

  14.beta.-[(p-Nitrocinnamoyl)amino]morphinones, 14.beta.-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogs: synthesis and receptor activity

  摘要：

  A series of 14beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5beta-Methyl group, were prepared from 14beta-aminocodeinones and 14beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5beta-methyl-14beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET-CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [H-3]DAMGO ([H-3]D-Ala2, (Me)-Phe4, Gly(ol)5]enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the B(max) value and a marginal effect on the K(d) value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.

  DOI：

  10.1021/jm00073a015
• 作为产物：
  描述：

  N-(cyclopropylmethyl)-5β-methyl-19-<(2,2,2-trichloroethoxy)carbonyl>-6,14-dihydro-6,14-(epoxyimino)northebaine 在 palladium on activated charcoal 氢气 、 sodium acetate 、 溶剂黄146 作用下， 以 甲醇 、 水 为溶剂， 反应 8.0h， 以700 mg的产率得到14β-amino-5β-methyl-7,8-dihydro-N-(cyclopropylmethyl)norcodeinone
  参考文献：
  名称：

  14.beta.-[(p-Nitrocinnamoyl)amino]morphinones, 14.beta.-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogs: synthesis and receptor activity

  摘要：

  A series of 14beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5beta-Methyl group, were prepared from 14beta-aminocodeinones and 14beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5beta-methyl-14beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET-CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [H-3]DAMGO ([H-3]D-Ala2, (Me)-Phe4, Gly(ol)5]enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the B(max) value and a marginal effect on the K(d) value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.

  DOI：

  10.1021/jm00073a015

文献信息

• 14β-Chlorocinnamoylamino derivatives of metopon: long-term μ-opioid receptor antagonists
  作者：Jay P McLaughlin、Alice Sebastian、Sydney Archer、Jean M Bidlack

  DOI：10.1016/s0014-2999(96)00904-1

  日期：1997.2

  The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited

  5β-甲基-14β-（对氯肉桂酸氨基）-7,8-二氢吗啡酮（MET-Cl-CAMO）和N-环丙基-甲基-5β-甲基-14β-（的亲和力，选择性和镇痛特性对-氯肉桂酸氨基）-7、8-二氢去甲吗啡酮（N-CPM-MET-Cl-CAMO）的多个阿片受体进行了表征。在使用牛纹状体膜的竞争结合测定中，两种化合物均抑制0.25 nM [3H] [D-Ala2，（Me）-Phe4，Gly（ol）5]脑啡肽（DAMGO）的结合，IC 50值小于2 nM 。用MET-CI-CAMO和N-CPM-MET-Cl-CAMO对膜进行预温育可产生对μ阿片受体结合的浓度依赖性，耐洗涤性抑制。用N-CPM-MET-Cl-CAMO进行的饱和结合实验表明，μ阿片类药物结合位点的数量减少了，亲和力却没有改变。在小鼠55度温水甩尾试验中，脑室内给药后，剂量不超过100 nmol的MET-Cl-CAMO和N-CPM-MET-Cl-