salvinorin B methylthiomethyl ether | 1017524-85-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: salvinorin B methylthiomethyl ether
• 英文别名: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(furan-3-yl)-6a,10b-dimethyl-9-(methylsulfanylmethoxy)-4,10-dioxo-2,4a,5,6,7,8,9,10a-octahydro-1H-benzo[f]isochromene-7-carboxylate
• CAS: 1017524-85-4
• 化学式: C₂₃H₃₀O₇S
• 分子量: 450.553
• InChiKey: IEZYEEBKOXBUJC-AGQYDFLVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  117
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  salvinorin B methylthiomethyl ether 在 N-碘代丁二酰亚胺 、 二乙胺基三氟化硫 作用下， 以 二氯甲烷 为溶剂， 以81%的产率得到salvinorin B fluoromethyl ether
  参考文献：
  名称：

  Standard protecting groups create potent and selective κ opioids: Salvinorin B alkoxymethyl ethers

  摘要：

  Protection of salvinorin B as standard alkoxyalkyl ethers yielded highly potent kappa opioid receptor agonists. Ethoxymethyl ether 6 is among the most potent and Selective kappa agonists reported to date. Fluoroethoxymethyl ether 11 is the first potent, selective fluorinated kappa ligand, with potential use in MRI and PET studies. Further enlargement of the alkoxy group, alkylation of the acetal carbon, or heteroatom substitution all reduced activity. These protecting groups may prove useful in related work not only by enabling the use of harsher synthetic conditions, but potentially by optimizing the potency of the products. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.10.067
• 作为产物：
  描述：

  SALVINORINB(品牌:CAYMAN进口) 、 二甲基亚砜 在 乙酸酐 、 溶剂黄146 作用下， 反应 65.0h， 以90%的产率得到salvinorin B methylthiomethyl ether
  参考文献：
  名称：

  Standard protecting groups create potent and selective κ opioids: Salvinorin B alkoxymethyl ethers

  摘要：

  Protection of salvinorin B as standard alkoxyalkyl ethers yielded highly potent kappa opioid receptor agonists. Ethoxymethyl ether 6 is among the most potent and Selective kappa agonists reported to date. Fluoroethoxymethyl ether 11 is the first potent, selective fluorinated kappa ligand, with potential use in MRI and PET studies. Further enlargement of the alkoxy group, alkylation of the acetal carbon, or heteroatom substitution all reduced activity. These protecting groups may prove useful in related work not only by enabling the use of harsher synthetic conditions, but potentially by optimizing the potency of the products. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.10.067

文献信息

• Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity
  作者：Thomas A Munro、Wei Xu、Douglas M Ho、Lee-Yuan Liu-Chen、Bruce M Cohen

  DOI：10.3762/bjoc.9.328

  日期：——

  The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A (1) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N-furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1. (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [³⁵S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1.

  最近的κ-阿片受体（κ-OR）的晶体结构揭示，出乎意料地，拮抗剂JDTic是一种双价配体：除了被吗啡类药物占据的正交袋外，JDTic还占据一个独特的（异位）口袋。突变数据表明，沙尔维诺林A（1）也结合到这个与经典阿片碱（Asp138）的碱性氮原子锚定的天冬氨酸残基相邻的异位口袋。有人建议，附加到1上的H键给体可能与Asp138相互作用，增加亲和力。这样的双价配体也可能具有改变的功能选择性。基于建模和已知的N-呋喃基甲基阿片拮抗剂，我们在1的呋喃环上附加了H键给体。在C-15或C-16处的二甲胺基甲基基团消除了对κ-OR的亲和力。在C-16处的羟甲基化是可以容忍的，但15,16-双羟甲基化则不行。由于配体调控剂可能在结合分析中未被检测到，我们还测试了这些以及其他对1的低亲和力衍生物对在[35S]GTPγS测定中对dynorphin A的配位调节作用。未检测到调节作用。作为双价衍生物的替代附着点，我们制备了2-（羟乙氧基）甲基醚，它保持了对κ-OR的高亲和力。我们讨论了关于1的联接、融合或合并的双价衍生物的替代设计策略。
• Standard protecting groups create potent and selective κ opioids: Salvinorin B alkoxymethyl ethers
  作者：Thomas A. Munro、Katharine K. Duncan、Wei Xu、Yulin Wang、Lee-Yuan Liu-Chen、William A. Carlezon Jr.、Bruce M. Cohen、Cécile Béguin

  DOI：10.1016/j.bmc.2007.10.067

  日期：2008.2.1

  Protection of salvinorin B as standard alkoxyalkyl ethers yielded highly potent kappa opioid receptor agonists. Ethoxymethyl ether 6 is among the most potent and Selective kappa agonists reported to date. Fluoroethoxymethyl ether 11 is the first potent, selective fluorinated kappa ligand, with potential use in MRI and PET studies. Further enlargement of the alkoxy group, alkylation of the acetal carbon, or heteroatom substitution all reduced activity. These protecting groups may prove useful in related work not only by enabling the use of harsher synthetic conditions, but potentially by optimizing the potency of the products. (c) 2007 Elsevier Ltd. All rights reserved.