[(4R,4aR,7S,7aR,12bS)-7-羟基-3-甲基-2,4,4A,5,6,7,7A,13-八氢-1H-4,12-甲桥苯并呋喃并[3,2-e]异喹啉-9-基]乙酸酯 | 58752-60-6

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 中文名称: [(4R,4aR,7S,7aR,12bS)-7-羟基-3-甲基-2,4,4A,5,6,7,7A,13-八氢-1H-4,12-甲桥苯并呋喃并[3,2-e]异喹啉-9-基]乙酸酯
• 英文名称: 3-O-acetyldihydromorphine
• 英文别名: (5alpha,6alpha)-4,5-Epoxy-6-hydroxy-17-methylmorphinan-3-yl acetate；[(4R,4aR,7S,7aR,12bS)-7-hydroxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl] acetate
• CAS: 58752-60-6
• 化学式: C₁₉H₂₃NO₄
• 分子量: 329.396
• InChiKey: KEJODKYTBSFQKS-LEPYJNQMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [(4R,4aR,7S,7aR,12bS)-7-羟基-3-甲基-2,4,4A,5,6,7,7A,13-八氢-1H-4,12-甲桥苯并呋喃并[3,2-e]异喹啉-9-基]乙酸酯 在 sodium tetrahydroborate 、 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 1.0h， 生成 6-β-sulfhydryldihydromorphine
  参考文献：
  名称：

  Ligand recognition in μ opioid receptor: experimentally based modeling of μ opioid receptor binding sites and their testing by ligand docking

  摘要：

  For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed opioid receptor-ligand interaction based on the receptor's 3D model. As a first step, we have constructed molecular models for the multiple opioid receptor subtypes using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping the three-dimensional structure of the mu opioid receptor, including the nature of the agonist-mediated conformational change that permits G protein-coupling to 'second messenger' effector molecules, and in identifying specific ligand-binding contacts with the mu opioid receptor. The analyses of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/s0968-0896(96)00219-2
• 作为产物：
  描述：

  3,6-alpha-二甲氧基-4,5-alpha-环氧-17-甲基-吗喃 在 ammonium hydroxide 、 二苯甲酮 、 potassium tert-butylate 、 氢溴酸 、 sodium hydroxide 作用下， 以 甲苯 为溶剂， 生成 [(4R,4aR,7S,7aR,12bS)-7-羟基-3-甲基-2,4,4A,5,6,7,7A,13-八氢-1H-4,12-甲桥苯并呋喃并[3,2-e]异喹啉-9-基]乙酸酯
  参考文献：
  名称：

  去甲氢吗啡酮 N-苯乙基部分中取代基的有趣作用：来自一组“尾巴摇狗”实验的双功能阿片类药物

  摘要：

  (−)-N-苯乙基类似物的光学纯 N-去甲氢吗啡酮被合成并在几个体外试验中进行药理学评估（阿片受体结合、[35S]GTPγS 结合的刺激、毛喉素诱导的 cAMP 积累试验和 MOR 介导的 β-抑制素募集测定）。“体”和“尾”与阿片受体的相互作用（Portoghese 信息地址理论的一个子集）被用于分子建模和模拟，其中“地址”可以被认为是氢吗啡酮分子的“主体”和“信息”由 N-苯乙基部分芳环上的取代基（尾）传递。一种化合物，Np-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3 ,2-e]isoquinolin-7(7aH)-one, 2i), 发现在 MOR 和 DOR 处具有纳摩尔结合亲和力。它是

  DOI：

  10.3390/molecules25112640

文献信息

• Synthesis and pharmacological evaluation of novel selective MOR agonist 6β-pyridinyl amidomorphines exhibiting long-lasting antinociception
  作者：Ákos Urai、András Váradi、Levente Szőcs、Balázs Komjáti、Valerie Le Rouzic、Amanda Hunkele、Gavril W. Pasternak、Susruta Majumdar、Sándor Hosztafi

  DOI：10.1039/c6md00450d

  日期：——

  6β-aminomorphinanes were prepared by stereoselective Mitsunobu reaction and subsequently acylated with nicotinic acid and isonicotinic acid chloride hydrochlorides. The receptor binding and efficacy were determined in vitro and the analgesic activity was studied in vivo. The in vitro studies revealed moderate selectivity for the MOR. At least two compounds in this series exhibited a long-lasting analgesic response

  以前有报道说6β-氨基吗啡喃衍生物对鸦片受体具有高亲和力。基于MOR选择性拮抗剂NAP设计了新型的6β-杂芳基吗啡酮。通过立体选择性Mitsunobu反应制备6β-氨基吗啡酮，然后用烟酸和异烟酸氯化物盐酸盐酰化。在体外测定受体结合和功效，并在体内研究镇痛作用。在体外研究表明，MOR具有中等选择性。当皮下和脑室内给药时，该系列中的至少两种化合物表现出持久的镇痛作用。当将这种物质经脑室内给药给小鼠时，它们显示出与吗啡相当的镇痛效果。
• Sulfate esters of morphine derivatives: Synthesis and characterization
  作者：András Váradi、András Gergely、Szabolcs Béni、Péter Jankovics、Béla Noszál、Sándor Hosztafi

  DOI：10.1016/j.ejps.2010.10.007

  日期：2011.1

  of sulfation with pyridine-SO(3) complex and sulfuric acid/N,N'-dicyclohexylcarbodiimide. Complete (1)H- and (13)C-NMR assignments are given for each of the synthesized compounds based on one- and two-dimensional homo- and heteronuclear measurements. Comparative analysis of chiral properties by circular dichroism and optical rotatory dispersion revealed characteristic differences in the spectra due

  通过吡啶-SO（3）络合物和硫酸/ N，N'-二环己基碳二亚胺的硫酸盐化反应，合成了十六种吗啡，可待因的3-O-和6-O-硫酸酯及其一些N-甲基季衍生物。基于一维和二维同核和异核测量，为每个合成的化合物给出了完整的（1）H-和（13）C-NMR分配。通过圆二色性和旋光色散对手性进行的比较分析表明，由于水溶液中强氢键的电荷，极性和分子内缔合的变化，光谱特征存在差异。将合成的硫酸酯是缺乏中央副作用潜在周止痛药，并且也作为用于涉及硫酸酯代谢物的各种分析研究参考物质是有用的。
• Preparation of benzoate esters of morphine and its derivatives
  作者：Szabolcs Béni、Gergő Tóth、Béla Noszál、Sándor Hosztafi

  DOI：10.1007/s00706-012-0803-8

  日期：2012.10

  synthesized compounds were determined by a reversed-phase high-performance liquid chromatography (HPLC)–MS-based method, and calculated hydrolysis rate constants are also provided. The synthesized benzoate esters are potential prodrugs of the parent morphine with enhanced lipophilicity, derivatives which can also be used in transdermal drug delivery as prospective long-acting narcotic analgesics. Graphical

  摘要持续镇痛对于遭受长效疼痛的患者至关重要。吗啡的酯衍生物可以增强吗啡的亲脂性。因此，其透皮递送及其作用持续时间也增加了。因此，二十一3- O-，6- O-和14- O合成了吗啡的苯甲酸酯及其衍生物，以阐明适用于这些广泛使用的化合物进行酯化的不同合成方法。Schotten-Baumann反应与碳酸氢钠，三乙胺或吡啶在二氯甲烷或1,2-二氯乙烷中的溶剂一起应用。主要在叔醇的情况下也成功地利用了4-二甲基氨基吡啶催化剂的存在。还提出了通过不含副产物的二乙酰基吗啡合成二氢吗啡的新方法。通过1 H核磁共振（NMR），13 C NMR，高分辨率质谱（HRMS）和电子电离质谱（EI-MS）阐明了所有合成化合物的结构。日志 D通过反相高效液相色谱（HPLC）–MS方法测定合成化合物的（pH 7.4）值，并提供计算出的水解速率常数。合成的苯甲酸酯是母体吗啡的潜在前药，具有增强的亲脂性，这些衍生物也可用于经皮给药，作为预期的长效麻醉镇痛药。
• Design and synthesis of sulfur-containing morphine and an opioid receptor probe.
  作者：Ikuo Fujii、Hiroko Togame、Mayumi Yamamoto、Ken Kanematsu、Issei Takayanagi、Fukio Konno

  DOI：10.1248/cpb.36.2282

  日期：——

  Sulfur-containing morphine derivatives were synthesized and their pharmacological properties were evaluated.

  硫含吗啡衍生物被合成，并对其药理学特性进行了评估。
• Glucosides of morphine derivatives: synthesis and characterization
  作者：András Váradi、Dóra Lévai、Gergő Tóth、Péter Horváth、Béla Noszál、Sándor Hosztafi

  DOI：10.1007/s00706-012-0868-4

  日期：2013.2

  Six 3-O- and 6-O-glucosides of morphine and codeine derivatives were synthesized by means of glucosylation with acetobromo-alpha-d-glucose. O-Glucosylation at C6 was carried out by the Koenigs-Knorr method, whereas the 3-O-glycoside of morphine was synthesized directly upon stirring morphine with acetobromo-alpha-d-glucose and aqueous sodium hydroxide in acetone. Complete H-1 and C-13 NMR assignments are presented for each synthesized compound based on one- and two-dimensional homo- and heteronuclear NMR techniques. Circular dichroism, ultraviolet absorbance, and high-resolution mass spectroscopy data ensure identification and structural characterization of the O-glucoside conjugates. The synthesized glucoside conjugates are potential analgesics; the presented spectral and chromatographic data are useful references for various analytical and metabolic studies including samples of biological origin.