17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-N-[(2’-quinolyl)acetamido]-morphinan-6-one hydrochloride

• 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: 17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-N-[(2’-quinolyl)acetamido]-morphinan-6-one hydrochloride
• 英文别名: 17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-N-[(2′-quinolyl)carboxamido]morphinan-6-one；N-[(4R,4aS,7aR,12bR)-3-(cyclopropylmethyl)-9-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-yl]quinoline-2-carboxamide;hydrochloride
• 化学式: C₃₀H₂₉N₃O₄*ClH
• 分子量: 532.039
• InChiKey: SIRVQLBXVQUOMT-FJNGYJFXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.93
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  91.8
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  蒂巴因 在 盐酸 、 sodium periodate 、 lithium aluminium tetrahydride 、 palladium 10% on activated carbon 、 氢气 、 sodium acetate 、 吡啶盐酸盐 、 三溴化硼 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 20.0 ℃ 、413.7 kPa 条件下， 反应 9.25h， 生成 17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-N-[(2’-quinolyl)acetamido]-morphinan-6-one hydrochloride
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity

  摘要：

  On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue-facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine-dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment.

  DOI：

  10.1021/jm4012214

文献信息

• Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity
  作者：Yunyun Yuan、Saheem A. Zaidi、Orgil Elbegdorj、Lindsey C. K. Aschenbach、Guo Li、David L. Stevens、Krista L. Scoggins、William L. Dewey、Dana E. Selley、Yan Zhang

  DOI：10.1021/jm4012214

  日期：2013.11.27

  On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue-facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine-dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment.