6α-oxymorphamine | 98634-03-8

• 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: 6α-oxymorphamine
• 英文别名: α-oxymorphamine；alpha-Oxymorphamine；(4R,4aS,7S,7aR,12bS)-7-amino-3-methyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol
• CAS: 98634-03-8
• 化学式: C₁₇H₂₂N₂O₃
• 分子量: 302.373
• InChiKey: KMVAXAKRXABEMD-NZQXGWJPSA-N

物化性质

• 沸点：
  497.4±45.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  79
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6α-oxymorphamine 在 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二异丙基碳二亚胺 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成 tert-butyl(5-(2-(2-((4αS,7S,7αR,12βS)-4α,9-dihydroxy-3-methyl-2,3,4,4α,5,6,7,7α-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)amino)-2-(oxoethoxy)acetamido)pentyl)carbamate
  参考文献：
  名称：

  Tuned-Affinity Bivalent Ligands for the Characterization of Opioid Receptor Heteromers

  摘要：

  Opioid receptors, including the mu- and delta-opioid receptors (MOR and DOR), are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers as compared to DOR homomers. Here, we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers as compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.

  DOI：

  10.1021/ml300083p
• 作为产物：
  描述：

  氢羟吗啡酮 在 sodium tetrahydroborate 、 5% Pd/C 、 氢气 、 对甲苯磺酸 作用下， 以 甲醇 、 乙醇 、 苯 为溶剂， 反应 85.0h， 生成 6α-oxymorphamine
  参考文献：
  名称：

  Tuned-Affinity Bivalent Ligands for the Characterization of Opioid Receptor Heteromers

  摘要：

  Opioid receptors, including the mu- and delta-opioid receptors (MOR and DOR), are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers as compared to DOR homomers. Here, we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers as compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.

  DOI：

  10.1021/ml300083p

文献信息

• Opioid agonist and antagonist bivalent ligands. The relationship between spacer length and selectivity at multiple opioid receptors
  作者：P. S. Portoghese、D. L. Larson、L. M. Sayre、C. B. Yim、G. Ronsisvalle、S. W. Tam、A. E. Takemori

  DOI：10.1021/jm00160a010

  日期：1986.10

  mu receptors as a function of spacer length. Also, delta receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the mu receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a kappa receptor agonist, occurred with the bivalent ligand

  合成了含有与不同长度的间隔基连接的羟吗啡胺或纳曲胺药效团的二价配体，并评估了它们在mu，κ和δ阿片样受体上的选择性。羟吗啡胺二价配体（1-8）在电刺激的豚鼠回肠纵向肌肉制剂（GPI）上起mu激动剂的作用。在这些系列中，赋予峰值激动剂活性的间隔基总共包含四个甘氨酰单元（n = 2）。对豚鼠脑膜的结合研究表明，在mu受体处，定性相似的谱是间隔子长度的函数。同样，随着间隔物的延长，δ受体选择性也增加。纳曲胺二价配体（9-13）以与激动剂系列相同的最佳间隔区长度（n = 2）有效拮抗GPI中的mu受体激动剂吗啡。然而，κ酮受体激动剂乙基酮唑嗪的峰值拮抗作用发生在含有最短间隔基（n = 0）的二价配体9上，发现9是该系列中选择性最高的κ拮抗剂。虽然受体结合在GPI中与kappa拮抗剂的活性大致相似，但在μ阿片受体上未观察到结合与拮抗剂活性之间的相关性。讨论了这些结果的可能意义。在μ阿片受体上未观察到
• [EN] ANALGESIC CONJUGATES<br/>[FR] CONJUGUÉS ANALGÉSIQUES
  申请人：UNIV MINNESOTA

  公开号：WO2014124317A1

  公开（公告）日：2014-08-14

  The invention provides analgesic conjugates having a mu opioid receptor agonist linked to a mGluR5 antagonist, and to methods for producing analgesia using such compounds.

  该发明提供了一种镇痛共轭物，其中包含与mGluR5拮抗剂连接的mu阿片受体激动剂，并提供了使用这种化合物产生镇痛作用的方法。
• Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK₂) Receptors by Novel Bivalent Ligands
  作者：Yaguo Zheng、Eyup Akgün、Kaleeckal G. Harikumar、Jessika Hopson、Michael D. Powers、Mary M. Lunzer、Laurence J. Miller、Philip S. Portoghese

  DOI：10.1021/jm800174p

  日期：2009.1.22

  between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16−22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand

  μ-阿片类药物 (MOP) 和 2 型胆囊收缩素 (CCK 2 ) 受体都存在于中枢神经系统区域，这些区域与疼痛处理的调节有关。我们对共表达 MOP 和 CCK 2受体的COS 细胞进行了生物发光共振能量转移 (BRET) 研究，以确定受体异二聚化是否参与这种调节。这些研究表明不存在组成型或单价配体诱导的异二聚化。因此，MOP 和 CCK 2受体的异二聚化不太可能是吗啡和 CCK 在 CNS 中的相反作用的原因。然而，如阳性 BRET 信号所示，当细胞暴露于含有 μ-阿片类激动剂和 CCK 的二价配体时，会诱导结合2受体拮抗剂药效团通过含有 16-22 个原子的间隔物连接，但不与较短（9 个原子）的间隔物相连。这些研究首次证明适当设计的二价配体能够诱导 G 蛋白偶联受体的结合。在小鼠中使用这些配体进行的阿片类药物耐受性研究表明与 BRET 数据没有相关性的发现与体内MOP 和 CCK 2受体不存在关联是一致的。
• ANALGESIC CONJUGATES
  申请人：PORTOGHESE Philip

  公开号：US20150374836A1

  公开（公告）日：2015-12-31

  The invention provides analgesic conjugates having a mu opioid receptor agonist linked to a mGluR 5 antagonist, and to methods for producing analgesia using such compounds.

  本发明提供了一种镇痛偶联物，其中包括一个与mu型阿片受体激动剂连接的mGluR5拮抗剂，并提供了使用这些化合物产生镇痛的方法。
• Bivalent Ligands That Target μ Opioid (MOP) and Cannabinoid1 (CB₁) Receptors Are Potent Analgesics Devoid of Tolerance
  作者：Morgan Le Naour、Eyup Akgün、Ajay Yekkirala、Mary M. Lunzer、Mike D. Powers、Alexander E. Kalyuzhny、Philip S. Portoghese

  DOI：10.1021/jm4005219

  日期：2013.7.11

  Given that mu opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both mu agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.