17-allyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(3-trifluoromethyl)benzamido]morphinan | 1373214-81-3

• 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-allyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(3-trifluoromethyl)benzamido]morphinan
• 英文别名: N-[(4R,4aS,7R,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-3-(trifluoromethyl)benzamide
• CAS: 1373214-81-3
• 化学式: C₂₇H₂₇F₃N₂O₄
• 分子量: 500.518
• InChiKey: GVNPFGAZPGVTKN-HJUABUFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  82
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  纳洛酮 在 ammonium acetate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 29.17h， 生成 17-allyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(3-trifluoromethyl)benzamido]morphinan
  参考文献：
  名称：

  Synthesis and Evaluation of Aryl-Naloxamide Opiate Analgesics Targeting Truncated Exon 11-Associated μ Opioid Receptor (MOR-1) Splice Variants

  摘要：

  3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3 Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower 5 opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the arylnaloxarnide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.

  DOI：

  10.1021/jm300305c

文献信息

• Synthesis and Evaluation of Aryl-Naloxamide Opiate Analgesics Targeting Truncated Exon 11-Associated μ Opioid Receptor (MOR-1) Splice Variants
  作者：Susruta Majumdar、Joan Subrath、Valerie Le Rouzic、Lisa Polikar、Maxim Burgman、Kuni Nagakura、Julie Ocampo、Nathan Haselton、Anna R. Pasternak、Steven Grinnell、Ying-Xian Pan、Gavril W. Pasternak

  DOI：10.1021/jm300305c

  日期：2012.7.26

  3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3 Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower 5 opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the arylnaloxarnide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.