(4aR,7S,7aR,12bS)-3-(3-((tert-butoxycarbonyl)amino)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate | 1313816-26-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: (4aR,7S,7aR,12bS)-3-(3-((tert-butoxycarbonyl)amino)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate
• 英文别名: (4aR,7S,7aR,12bS)-3-(4-((tert-butoxycarbonyl)amino)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate；[(4R,4aR,7S,7aR,12bS)-9-acetyloxy-3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl] acetate
• CAS: 1313816-26-0
• 化学式: C₂₉H₃₈N₂O₇
• 分子量: 526.63
• InChiKey: LTFBMEYVZRNQEC-CIVUWBIHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (4aR,7S,7aR,12bS)-3-(3-((tert-butoxycarbonyl)amino)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate 在 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 (4aR,7S,7aR,12bS)-3-(3-(3-mercaptopropanamido)butyl)-2,3,4,4a,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate
  参考文献：
  名称：

  [EN] HEROIN HAPTENS, IMMUNOCONJUGATES AND RELATED USES
  [FR] HAPTÈNES D'HÉROÏNE, IMMUNOCONJUGUÉS ET UTILISATIONS ASSOCIÉES

  摘要：

  本发明提供了新型海洛因半抗原化合物和海洛因免疫结合物，可用于体内产生特异性结合海洛因及其精神活性代谢物的抗体。本发明还提供了使用包含海洛因免疫结合物的疫苗进行主动或被动免疫方案的方法。本发明的组合物和方法对于预防和治疗海洛因成瘾是有用的。

  公开号：

  WO2013095321A1
• 作为产物：
  描述：

  二乙酰基吗啡 在 三乙酰氧基硼氢化钠 、 三乙胺 作用下， 生成 (4aR,7S,7aR,12bS)-3-(3-((tert-butoxycarbonyl)amino)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate
  参考文献：
  名称：

  Development of a Clinically Viable Heroin Vaccine

  摘要：

  Heroin is a highly abused opioid and incurs a significant detriment to society worldwide. In an effort to expand the limited pharmacotherapy options for opioid use disorders, a heroin conjugate vaccine was developed through comprehensive evaluation of hapten structure, carrier protein, adjuvant and dosing. Immunization of mice with an optimized heroin-tetanus toxoid (TT) conjugate formulated with adjuvants alum and CpG oligodeoxynucleotide (ODN) generated heroin immunoantagonism, reducing heroin potency by >15-fold. Moreover, the vaccine effects proved to be durable, persisting for over eight months. The lead vaccine was effective in rhesus monkeys, generating significant and sustained antidrug IgG titers in each subject. Characterization of both mouse and monkey antiheroin antibodies by surface plasmon resonance (SPR) revealed low nanomolar antiserum affinity for the key heroin metabolite, 6-acetylmorphine (6AM), with minimal cross reactivity to clinically used opioids. Following a series of heroin challenges over six months in vaccinated monkeys, drug-sequestering antibodies caused marked attenuation of heroin potency (>4-fold) in a schedule-controlled responding (SCR) behavioral assay. Overall, these preclinical results provide an empirical foundation supporting the further evaluation and potential clinical utility of an effective heroin vaccine in treating opioid use disorders.

  DOI：

  10.1021/jacs.7b03334

文献信息

• [EN] AN IMPROVED HEROIN VACCINE<br/>[FR] VACCIN CONTRE L'HÉROÏNE AMÉLIORÉ
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2019094528A1

  公开（公告）日：2019-05-16

  An improved heroin conjugate vaccine is detailed; to accomplish this task the systematic exploration of twenty vaccine formulations with varying combinations of carrier proteins and adjuvants were undertaken. In regard to adjuvants, a Toll-like receptor 9 (TLR9) agonist and a TLR3 agonist in the presence of alum were explored. The vaccine formulations containing TLR3 or TLR9 agonist alone-elicited strong anti-heroin antibody titers and blockade of heroin-induced antinociception when formulated with alum; however, a combination of TLR3 and 9 adjuvants did not result in improved efficacy. Investigation of stability of the two lead formulations revealed that the TLR9 but not the TLR3 formulation was stable when stored over 30 days. Furthermore, mice immunized with the TLR9 + alum heroin vaccine gained significant protection from lethal heroin doses, suggesting that this vaccine formulation is suitable for mitigating the lethal effects of heroin, even following long-term storage at room temperature.

  详细介绍了一种改进的海洛因结合疫苗；为了完成这项任务，进行了对二十种疫苗配方的系统探索，这些配方采用了不同载体蛋白和佐剂的组合。在佐剂方面，研究了存在于氢氧化铝中的Toll样受体9（TLR9）激动剂和Toll样受体3（TLR3）激动剂。含有单独的TLR3或TLR9激动剂的疫苗配方在与氢氧化铝配方时引发了强烈的抗海洛因抗体滴度和阻断海洛因诱导的止痛作用；然而，TLR3和9激动剂的组合并没有导致疫效的改善。对两种主要配方的稳定性进行的调查显示，存放超过30天时，TLR9配方而不是TLR3配方是稳定的。此外，接种了TLR9 + 氢氧化铝海洛因疫苗的小鼠对致命海洛因剂量获得了显著的保护，表明这种疫苗配方适用于减轻海洛因的致命影响，即使在室温下长期存放后也是如此。
• A Vaccine Strategy that Induces Protective Immunity against Heroin
  作者：G. Neil Stowe、Leandro F. Vendruscolo、Scott Edwards、Joel E. Schlosburg、Kaushik K. Misra、Gery Schulteis、Alexander V. Mayorov、Joseph S. Zakhari、George F. Koob、Kim D. Janda

  DOI：10.1021/jm200461m

  日期：2011.7.28

  Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long-lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target, as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma, we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach through the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten.