16-(hydroxymethyl)salvinorin A

• 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: 16-(hydroxymethyl)salvinorin A
• 英文别名: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-9-acetyloxy-2-[2-(hydroxymethyl)furan-3-yl]-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octahydro-1H-benzo[f]isochromene-7-carboxylate
• 化学式: C₂₄H₃₀O₉
• 分子量: 462.497
• InChiKey: BIYXSCDIHODPOH-ZWLNRFIDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  129
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  16-(hydroxymethyl)salvinorin A 在 草酰氯 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 3.5h， 以81%的产率得到(2S,4aR,6aR,7R,9S,10aS,10bR)-methyl 9-acetoxy-2-(2-formylfuran-3-yl)-6a,10b-dimethyl-4,10-dioxododecahydro-1H-benzo[f]isochromene-7-carboxylate
  参考文献：
  名称：

  Synthesis and κ-Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues

  摘要：

  The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent kappa-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the kappa-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other kappa-opioid agonists.

  DOI：

  10.1021/jm501521d
• 作为产物：
  描述：

  聚合甲醛 、 丹酚 A 在 溶剂黄146 、 水 作用下， 反应 21.0h， 以21%的产率得到16-(hydroxymethyl)salvinorin A
  参考文献：
  名称：

  Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

  摘要：

  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。

  DOI：

  10.3762/bjoc.9.328

文献信息

• COMBINATION PRODUCT FOR THE INDUCTION AND/OR MAINTENANCE OF GENERAL ANESTHESIA
  申请人：BLUMENTECH, S.L.

  公开号：US20210186927A1

  公开（公告）日：2021-06-24

  The state of general anesthesia (GA) is essential to many surgical and medical procedures. This state is characterized by loss of consciousness, deep analgesia and suppression of movements. GA is rarely achieved with a single drug, usually requiring the combination of various pharmacological agents. Each drug can interact with one or more molecular targets affecting neuronal excitability and synaptic transmission in multiple regions of the CNS. Agonists of the μ-opioid receptor are commonly used in GA to cause analgesia, but not to induce or maintain loss of consciousness or movement suppression. Additionally, agonists of the μ-opioid receptor can cause serious unwanted side effects, e.g. respiratory depression. The present invention provides alternative combination products based on K-opioid receptor agonists. These combination products unexpectedly induced loss of consciousness, and were able to achieve and maintain GA. Furthermore, the combination products suppressed pain perception without the need of a μ-opioid receptor agonist. The combination of Salvinorin A, a selective κ-opioid receptor agonist, with Diazepam or Medetomidine surprisingly led to rapid consciousness, deep analgesia and movement suppression. This combination was found to effectively induce and maintain a state of general anesthesia.
• Synthesis and κ-Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues
  作者：Andrew P. Riley、Chad E. Groer、David Young、Amy W. Ewald、Bronwyn M. Kivell、Thomas E. Prisinzano

  DOI：10.1021/jm501521d

  日期：2014.12.26

  The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent kappa-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the kappa-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other kappa-opioid agonists.
• 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。