17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(6,7-dimethoxyisoquinoline-3-carboxamido)morphinan

• 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-3,14β-dihydroxy-4,5α-epoxy-6α-(6,7-dimethoxyisoquinoline-3-carboxamido)morphinan
• 英文别名: N-[(4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-6,7-dimethoxyisoquinoline-3-carboxamide
• 化学式: C₃₂H₃₅N₃O₆
• 分子量: 557.646
• InChiKey: PDQAKNFWMDCGQC-MVEZPGGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  113
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(6,7-dimethoxyisoquinoline-3-carboxamido)morphinan 在 盐酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 0.08h， 生成 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(6,7-dimethoxyisoquinoline-3-carboxamido)morphinan hydrochloride
  参考文献：
  名称：

  Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

  摘要：

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2015.02.055
• 作为产物：
  描述：

  纳曲酮 在 盐酸 、 sodium tetrahydroborate 、 palladium on activated charcoal 、 氢气 、 1-羟基苯并三唑 、 对甲苯磺酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 0.25h， 生成 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(6,7-dimethoxyisoquinoline-3-carboxamido)morphinan
  参考文献：
  名称：

  Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

  摘要：

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2015.02.055

文献信息

• NON-PEPTIDYL, POTENT, AND SELECTIVE MU OPIOID RECEPTOR ANTAGONISTS AND THEIR USE IN TREATING OPIOID ADDICTION AND OPIOID INDUCED CONSTIPATION
  申请人：Virginia Commonwealth University

  公开号：US20140371255A1

  公开（公告）日：2014-12-18

  Selective, non-peptide antagonists of the mu opioid receptor (MOR) and methods of their use are provided. The antagonists may be used, for example, to identify MOR agonists in competitive binding assays, and to treat conditions related to addiction in which MOR is involved, e.g. heroin, prescription drug and alcohol addiction, as well as in the treatment of opioid induced constipation (OIC).

  提供了选择性的、非肽类的μ阿片受体（MOR）拮抗剂及其使用方法。这些拮抗剂可用于识别竞争性结合测定中的MOR激动剂，以及治疗与MOR有关的成瘾症状，例如海洛因、处方药物和酒精成瘾，以及治疗因阿片类药物引起的便秘（OIC）。
• US8980908B2
  申请人：——

  公开号：US8980908B2

  公开（公告）日：2015-03-17
• Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
  作者：Yunyun Yuan、Saheem A. Zaidi、David L. Stevens、Krista L. Scoggins、Philip D. Mosier、Glen E. Kellogg、William L. Dewey、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmc.2015.02.055

  日期：2015.4

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.