(5alpha,6alpha)-7,8-二去氢-4,5-环氧-3-乙氧基-吗喃-6-醇 | 72165-34-5

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 中文名称: (5alpha,6alpha)-7,8-二去氢-4,5-环氧-3-乙氧基-吗喃-6-醇
• 中文别名: β.-核-六吡喃糖,1,6-脱水-3-脱氧-4-O-甲基-2-O-(苯基甲基)-
• 英文名称: norethylmorphine
• 英文别名: 3α-ethoxy-4,5α-epoxy-morphin-7-en-6-ol；3α-Aethoxy-4,5α-epoxy-morphin-7-en-6-ol；(4R,4aR,7S,7aR,12bS)-9-ethoxy-1,2,3,4,4a,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol
• CAS: 72165-34-5
• 化学式: C₁₈H₂₁NO₃
• 分子量: 299.37
• InChiKey: YCZKZYXHGKGDNL-DNJOTXNNSA-N

物化性质

• 沸点：
  476.7±45.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、乙醇（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  50.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  乙基吗啡 生成 (5alpha,6alpha)-7,8-二去氢-4,5-环氧-3-乙氧基-吗喃-6-醇
  参考文献：
  名称：

  Evidence for CYP2D1-mediated primary and secondary O-dealkylation of ethylmorphine and codeine in rat liver microsomes

  摘要：

  The purpose of the present study was to investigate the role of specific CYPs responsible for the O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M), as well as that of norethylmorphine (NEM) and norcodeine (NCD) to normorphine (NM) in rat liver microsomes. Liver microsomes metabolize EM and CD to M, and NEM and NCD to NM, in the presence of an NADPH-generating system. The metabolites of EM and CD were determined by HPLC with UV and electrochemical detection. In the present study, the role of CYP2D1 in O-dealkylation of EM/NEM and CD/NCD was investigated by use of specific antiCYP antibodies. When testing rabbit antirat CYP2D1, 2E1, 2C11, and 3A2 antibodies, only the antiCYP2D1 antibody inhibited the EM/NEM and CD/NCD O-dealkylase activities significantly. The maximum inhibition achieved was similar to 80% at a protein ratio (IgG to microsomes) of 10:1, p = 0.001. The contribution of CYP2D1 to the O-dealkylation of EM/NEM and CD/NCD was further confirmed by use of the specific CYP2D1 inhibitors quinine and propafenone. Five mu M of quinine inhibited the EM/NEM and CD/NCD O-dealkylase activities by similar to 80%. The CYP3A inhibitor troleandomycin (TAO) failed to inhibit the CYP2D1 catalyzed reaction, but did inhibit the N-demethylation of EM and CD. The O-dealkylation of NEM and NCD was also impaired in Dark Agouti rat (DA) liver microsomes. Taken together, the immunoinhibition and chemical-inhibitor studies of rat liver microsomes provided convincing evidence for the involvement of CYP2DL, the rat counterpart of human CYP2D6, in the metabolism of EM/NEM and CD/NCD to the corresponding O-dealkylated metabolites. (C) 1997 Elsevier Science Inc.

  DOI：

  10.1016/s0006-2952(96)00736-8

文献信息

• Ethylmorphine o-deethylation in isolated rat hepatocytes
  作者：Bang Qian Xu、Tor A. Aasmundstad、Anders Bjørneboe、Asbjørg S. Christophersen、Jørg Mørland

  DOI：10.1016/0006-2952(94)00481-z

  日期：1995.2

  The O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M) co-segregates with debrisoquine/sparteine genetic polymorphism in man. CD O-demethylation is catalysed by cytochrome P450 2D1 (CYP2D1) in rats. In the present study, the O-deethylation of EM was examined and compared with that of CD in suspensions of freshly-isolated hepatocytes prepared by a collagenase method from Wistar rats with and without CYP2D1 inhibitors. Isolated hepatocytes were also prepared from Dark Agouti (DA) rats deficient in CYP2D1, and were incubated with EM or CD. EM, CD and their metabolites were quantified by HPLC with UV detection. EM had a similar pattern of metabolism to that of CD in suspensions of hepatocytes from Wistar rats. Both EM and CD were O-dealkylated to form M plus morphine-3-glucuronide (M3G) and N-demethylated to form norethylmorphine (NEM) or norcodeine (NCD), respectively, which were further metabolized to normorphine (NM) and finally glucuronidated to normorphine 3-glucuronide (NM3G). As compared to hepatocytes from Wistar rats, DA rats were characterized by a markedly decreased formation (70-75% reduction) of M plus M3G from both EM and CD. Quinine, quinidine, propafenone and sparteine all inhibited EM O-deethylation as well as CD O-demethylation. Quinine was the most potent inhibitor of both these O-dealkylations (K-i = 0.2 mu M for both EM and CD, respectively). Quinine as well as the other inhibitors inhibited both EM and CD O-dealkylation competitively and with small differences in K-i versus EM and CD, respectively. The metabolism of EM to M plus M3G and that of CD to M plus M3G was highly correlated when results from the various separate cell suspensions were plotted. In conclusion all findings indicated that the enzyme responsible for O-demethylation of CD, CYP2D1 was also responsible for the O-deethylation of EM to M.
• v. Braun, Chemische Berichte, 1916, vol. 49, p. 987
  作者：v. Braun

  DOI：——

  日期：——
• Evidence for CYP2D1-mediated primary and secondary O-dealkylation of ethylmorphine and codeine in rat liver microsomes
  作者：Bang Qian Xu、Tor A. Aasmundstad、Asbjørg S. Christophersen、Jørg Mørland、Anders Bjørneboe

  DOI：10.1016/s0006-2952(96)00736-8

  日期：1997.2

  The purpose of the present study was to investigate the role of specific CYPs responsible for the O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M), as well as that of norethylmorphine (NEM) and norcodeine (NCD) to normorphine (NM) in rat liver microsomes. Liver microsomes metabolize EM and CD to M, and NEM and NCD to NM, in the presence of an NADPH-generating system. The metabolites of EM and CD were determined by HPLC with UV and electrochemical detection. In the present study, the role of CYP2D1 in O-dealkylation of EM/NEM and CD/NCD was investigated by use of specific antiCYP antibodies. When testing rabbit antirat CYP2D1, 2E1, 2C11, and 3A2 antibodies, only the antiCYP2D1 antibody inhibited the EM/NEM and CD/NCD O-dealkylase activities significantly. The maximum inhibition achieved was similar to 80% at a protein ratio (IgG to microsomes) of 10:1, p = 0.001. The contribution of CYP2D1 to the O-dealkylation of EM/NEM and CD/NCD was further confirmed by use of the specific CYP2D1 inhibitors quinine and propafenone. Five mu M of quinine inhibited the EM/NEM and CD/NCD O-dealkylase activities by similar to 80%. The CYP3A inhibitor troleandomycin (TAO) failed to inhibit the CYP2D1 catalyzed reaction, but did inhibit the N-demethylation of EM and CD. The O-dealkylation of NEM and NCD was also impaired in Dark Agouti rat (DA) liver microsomes. Taken together, the immunoinhibition and chemical-inhibitor studies of rat liver microsomes provided convincing evidence for the involvement of CYP2DL, the rat counterpart of human CYP2D6, in the metabolism of EM/NEM and CD/NCD to the corresponding O-dealkylated metabolites. (C) 1997 Elsevier Science Inc.