2-(3-(dimethylamino)-2,2-dimethylpropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione | 505059-19-8

• 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: 2-(3-(dimethylamino)-2,2-dimethylpropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
• 英文别名: N-[3-(N',N'-dimethylamino)-2,2-dimethylpropyl]-benzo[de]isoquinoline-1,3-dione；2-(3-dimethylamino-2,2-dimethylpropyl)benzo[de]isoquinoline-1,3-dione；1,8-naphthalimidopropilamine；1,8-naphthalimidopropylamine；2-[3-(dimethylamino)-2,2-dimethylpropyl]benzo[de]isoquinoline-1,3-dione
• CAS: 505059-19-8
• 化学式: C₁₉H₂₂N₂O₂
• 分子量: 310.396
• InChiKey: YVCVVAMFKSYHAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(3-(dimethylamino)-2,2-dimethylpropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione 以 乙腈 为溶剂， 生成 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：

  1,8-萘二甲酸酐 、 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 9.0h， 以61%的产率得到2-(3-(dimethylamino)-2,2-dimethylpropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
  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。
• Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M₁and M₂
  作者：Regina Messerer、Clelia Dallanoce、Carlo Matera、Sarah Wehle、Lisa Flammini、Brian Chirinda、Andreas Bock、Matthias Irmen、Christian Tränkle、Elisabetta Barocelli、Michael Decker、Christoph Sotriffer、Marco De Amici、Ulrike Holzgrabe

  DOI：10.1039/c7md00149e

  日期：——

  the skeletons of the orthosteric muscarinic agonists, iperoxo and isox, on the other hand, were synthesized. The two molecular moieties were connected via a polymethylene linker of varying length. These bipharmacophoric compounds were investigated for inhibition of AChE (from electric eel) and BChE (from equine serum) as well as human ChEs in vitro and compared to previously synthesized dimeric inhibitors

  一组杂合化合物，其一方面由毒蕈碱受体的变构调节剂的片段（即W84和萘甲铵）与著名的AChE抑制剂他克林组成，另一方面由正构毒蕈碱激动剂的骨架，peroxox和isox组成。另一方面，是合成的。这两个分子部分通过不同长度的聚亚甲基接头连接。在体外研究了这些双药效化合物对AChE（来自鳗鱼）和BChE（来自马血清）以及人类ChEs的抑制作用，并将其与先前合成的二聚体抑制剂进行了比较。在研究的杂种中，化合物10-C10，其特点是由10个碳的亚烷基接头连接他克林和哌咯酮，被证明是最有效的抑制剂，其pIC 50值最高，为9.81（来自鳗鱼的AChE）和8.75（来自马血清的BChE）。对接用化合物实验10-C10，7B-C10，和图7a-C10有助于解释对乙酰胆碱酯酶，其通过变构分子部分的性质影响了实验的抑制力，与含他克林杂交就比活性更高的含萘二甲酰亚胺和邻苯二甲酰亚胺的类似物。此外，发现最活跃的AChE抑制剂对M
• 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。
• Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist
  作者：Fabio Riefolo、Carlo Matera、Aida Garrido-Charles、Alexandre M. J. Gomila、Rosalba Sortino、Luca Agnetta、Enrique Claro、Roser Masgrau、Ulrike Holzgrabe、Montserrat Batlle、Michael Decker、Eduard Guasch、Pau Gorostiza

  DOI：10.1021/jacs.9b03505

  日期：2019.5.8

  offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule

  生理功能的光触发可逆调节有望实现按需时空控制的治疗干预。光遗传学已在心脏中成功实施，但其在临床中的应用仍然存在重大障碍，例如需要进行基因转染。在此，我们提出了一种通过光开关化合物在不进行基因操作的情况下用光调节心脏功能的方法。这种名为 PAI 的分子是通过在 M2 mAChR 激动剂的分子结构中引入光开关而设计的。体外试验表明，PAI 能够实现 M2 mAChR 的光依赖性激活。为了验证该方法，我们展示了 PAI 光异构体在哺乳动物模型中显示出不同的心脏效应，并证明是可逆的，半透明野生型蝌蚪心脏功能的实时光控制。PAI还可以利用近红外光的双光子激发有效激活M2受体，克服了短波照明的散射和低穿透性，为活体成像和心脏功能控制提供了新的机会。
• 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.