17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-N-[(2’-naphthalyl)acetamido]morphinan-6-one | 1443792-88-8

• 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’-naphthalyl)acetamido]morphinan-6-one
• 英文别名: 17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-N-[2′-naphthamido]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]naphthalene-2-carboxamide
• CAS: 1443792-88-8
• 化学式: C₃₁H₃₀N₂O₄
• 分子量: 494.59
• InChiKey: ONUPTIBKDOMBGJ-QQZIBPAVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  5

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’-naphthalyl)acetamido]morphinan-6-one
  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

• Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives
  作者：Yan Zhang、Orgil Elbegdorj、Yunyun Yuan、Irina O. Beletskaya、Dana E. Selley

  DOI：10.1016/j.bmcl.2013.05.027

  日期：2013.7

  Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the S-35-GTP[gamma S] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. Published by Elsevier Ltd.
• 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.