6-bromo-N-[3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-2,2-dimethylpropyl]-N,N-dimethylhexane-1-aminium bromide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 6-bromo-N-[3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-2,2-dimethylpropyl]-N,N-dimethylhexane-1-aminium bromide
• 英文别名: (6-bromohexyl)-[3-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-2,2-dimethyl-propyl]dimethyl-ammonium bromide；(6-bromohexyl)-[3-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-2,2-dimethylpropyl]dimethylammonium bromide；6-Bromohexyl-[3-(1,3-dioxobenzo[de]isoquinolin-2-yl)-2,2-dimethylpropyl]-dimethylazanium;bromide
• 化学式: Br*C₂₅H₃₄BrN₂O₂
• 分子量: 554.365
• InChiKey: FIJYTBVUMUXEGT-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Atropine 、 6-bromo-N-[3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-2,2-dimethylpropyl]-N,N-dimethylhexane-1-aminium bromide 以 乙腈 为溶剂， 以60%的产率得到8-[6-(N-(3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-2,2-dimethylpropyl)-N,N-dimethylammonio)hexyl]-3-[(3-hydroxy-2-phenylpropanoyl)oxy]-8-methyl-8-azabicyclo[3.2.1]octan-8-ium dibromide
  参考文献：
  名称：

  Dualsteric Muscarinic Antagonists–Orthosteric Binding Pose Controls Allosteric Subtype Selectivity

  摘要：

  Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure-activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.

  DOI：

  10.1021/jm500790x
• 作为产物：
  描述：

  N,N,2,2-四甲基-1,3-丙二胺 在 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 273.0h， 生成 6-bromo-N-[3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-2,2-dimethylpropyl]-N,N-dimethylhexane-1-aminium bromide
  参考文献：
  名称：

  毒蕈碱配体结合的高亲和力双（氨）烷型变构增强剂的系统开发。

  摘要：

  在氮原子上带有侧苯二甲酰亚胺丙基取代基的双（铵）烷烃化合物属于原型毒蕈碱变构剂。在此，合成了一系列对称和非对称化合物，其中邻苯二甲酰亚胺残基被不同取代的酰亚胺部分取代。使用[（3）H] N-甲基东pol碱（NMS）作为正构受体在平衡结合和解离实验中的配体，在猪心脏毒蕈碱M（2）受体中测量了变构作用。1,8-萘二甲酰亚胺基残基的亲和力最多增加100倍，从而导致低纳摩尔范围，同时保持了对NMS结合的抑制作用。附加的丙基链甲基化伴随着正构配体结合的变构升高。一般来说，通过环的变化加上分子一侧的丙基链甲基化所获得的变构活性的增益不能通过对称的变化来增加。配体结合的升高可以通过与游离和直链受体结合的亲和力的不同定量结构-活性关系来解释。

  DOI：

  10.1021/jm021017q

文献信息

• Systematic Development of High Affinity Bis(ammonio)alkane-type Allosteric Enhancers of Muscarinic Ligand Binding
  作者：Mathias Muth、Wiebke Bender、Olaf Scharfenstein、Ulrike Holzgrabe、Edith Balatkova、Christian Tränkle、Klaus Mohr

  DOI：10.1021/jm021017q

  日期：2003.3.1

  the orthosteric receptor site in equilibrium binding and dissociation experiments. 1,8-Naphthalimido residues conferred an up to 100-fold gain in affinity leading into the low nanomolar range, while the inhibition of NMS binding was maintained. Additional propyl chain methylation was accompanied by an allosteric elevation of orthosteric ligand binding. In general, the gain in allosteric activity achieved

  在氮原子上带有侧苯二甲酰亚胺丙基取代基的双（铵）烷烃化合物属于原型毒蕈碱变构剂。在此，合成了一系列对称和非对称化合物，其中邻苯二甲酰亚胺残基被不同取代的酰亚胺部分取代。使用[（3）H] N-甲基东pol碱（NMS）作为正构受体在平衡结合和解离实验中的配体，在猪心脏毒蕈碱M（2）受体中测量了变构作用。1,8-萘二甲酰亚胺基残基的亲和力最多增加100倍，从而导致低纳摩尔范围，同时保持了对NMS结合的抑制作用。附加的丙基链甲基化伴随着正构配体结合的变构升高。一般来说，通过环的变化加上分子一侧的丙基链甲基化所获得的变构活性的增益不能通过对称的变化来增加。配体结合的升高可以通过与游离和直链受体结合的亲和力的不同定量结构-活性关系来解释。
• Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity
  作者：Carlo Matera、Lisa Flammini、Marta Quadri、Valentina Vivo、Vigilio Ballabeni、Ulrike Holzgrabe、Klaus Mohr、Marco De Amici、Elisabetta Barocelli、Simona Bertoni、Clelia Dallanoce

  DOI：10.1016/j.ejmech.2014.01.032

  日期：2014.3

  tested in vitro and in vivo two groups of bis(ammonio)alkane-type compounds, 6a–9a and 6b–9b, which incorporate the orthosteric muscarinic agonist iperoxo into a molecular fragment of the M2-selective allosteric modulators W84 and naphmethonium. The agonist potency and efficacy of these hybrid derivatives at M1, M2 and M3 muscarinic receptor subtypes and their anticholinesterase activity were evaluated

  在这项研究中，我们合成并测试在体外和体内两组双（铵）烷烃型化合物，6A -图9a和图6b -图9b，其包含正构毒蕈碱型激动剂iperoxo到M的分子片段2 -选择性变构调节剂W84和萘甲铵。在分离的组织制剂上评估了这些杂合衍生物对M 1，M 2和M 3毒蕈碱受体亚型的激动剂效力和功效以及它们的抗胆碱酯酶活性。然后在体内测定其镇痛作用在乙酸扭体试验中，还确定了周围和中枢胆碱能副作用的发生。研究的杂种表现为强毒蕈碱激动剂和弱胆碱酯酶抑制剂。这些作用对于带有萘甲铵部分的双季盐比含W84的类似物更为明显，并导致体内显着的止痛活性。萘甲铵相关的化合物8b显示出令人鼓舞的概况，该化合物结合了受试化合物中最有效的镇痛作用，而没有相关的胆碱能副作用。
• Design, Synthesis, and Action of Oxotremorine-Related Hybrid-Type Allosteric Modulators of Muscarinic Acetylcholine Receptors
  作者：Teresa Disingrini、Mathias Muth、Clelia Dallanoce、Elisabetta Barocelli、Simona Bertoni、Kerstin Kellershohn、Klaus Mohr、Marco De Amici、Ulrike Holzgrabe

  DOI：10.1021/jm050769s

  日期：2006.1.1

  A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M-2 receptors using [H-3]N-methylseopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a-10a and 8b-10b. The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M-1-M-3 muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [S-35]GTP gamma S binding assays using human M-2 receptors overexpressed. in CHO cells revealed that a weak intrinsic efficacy was preserved in 8b-10b. Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixed.
• The bisnaphthalimides as new active lead compounds against Plasmodium falciparum
  作者：Maximilian Tischer、Ludmilla Sologub、Gabriele Pradel、Ulrike Holzgrabe

  DOI：10.1016/j.bmc.2010.03.067

  日期：2010.5

  The bisquaternary bisnaphthalimides are a versatile class of compounds being active against the malaria parasite Plasmodium falciparum in the lower nanomolar range of concentration combined with no cytotoxicity. The series of compounds is designed as choline analogues and interfering agents of the phosphatidylcholine biosynthesis. The qualitative analysis of the structure-activity relationships (SAR) revealed the importance of a long methylene middle chain of at least 8 methylene groups between the two bisquaternary naphthalimides or a monoquaternary naphthalimide consisting of a long alkyl chain attached to the positively charged nitrogen atom. Since the SARs are different from reported biscationic antimalarial drugs the mode of action remains to be elucidated. (c) 2010 Elsevier Ltd. All rights reserved.
• Antitrypanosomal activity of quaternary naphthalimide derivatives
  作者：Mathias Muth、Verena Hoerr、Melanie Glaser、Alicia Ponte-Sucre、Heidrun Moll、August Stich、Ulrike Holzgrabe

  DOI：10.1016/j.bmcl.2006.12.088

  日期：2007.3

  Sleeping sickness caused by Trypanosoma brucei gambiense and rhodesiense is fatal if left untreated. Due to the toxicity of drugs currently used and the emerging resistance against these drugs new lead compounds are urgently needed. Within the frame of a broad screening program for drugs with antitrypanosomal activity, some highly potent tertiary and quaternary mono- and bis-naphthalimides being active in the lower micromolar and nanomolar range of concentration have been identified. These compounds are easily available via a two- or three-step microwave-driven synthesis with high yield. (c) 2007 Elsevier Ltd. All rights reserved.