((4aR,7S,7aR,12bS)-3-(3-(3-tritylthio)propanamido)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate | 1313816-36-2

• 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-(3-tritylthio)propanamido)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate
• 英文别名: [(4R,4aR,7S,7aR,12bS)-9-acetyloxy-3-[4-(3-tritylsulfanylpropanoylamino)butyl]-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl] acetate
• CAS: 1313816-36-2
• 化学式: C₄₆H₄₈N₂O₆S
• 分子量: 756.963
• InChiKey: GSEFAURHIFWSLJ-DCZUXPHDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  55
• 可旋转键数：
  16
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  120
• 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-(3-tritylthio)propanamido)butyl)-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diyl diacetate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 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-(3-tritylthio)propanamido)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

• Investigating the Effects of a Hydrolytically Stable Hapten and a Th1 Adjuvant on Heroin Vaccine Performance
  作者：Paul T. Bremer、Kim D. Janda

  DOI：10.1021/jm301262z

  日期：2012.12.13

  We challenged the performance of our previous heroin vaccine with a similar vaccine containing a more hydrolytically stable hapten analogue and a Th1 adjuvant (CpG ODN). Our results indicate that the elements of our previous vaccine are essential for its anti-heroin potency, i.e., a chemically labile hapten and an exclusively Th2 humoral response elicited by alum. Such design elements are critical for producing next-generation heroin vaccines.
• 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.