6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan hydrochloride

• 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: 6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan hydrochloride
• 英文别名: N-noroxymorphindole hydrochloride；(1S,2S,13R,21R)-14-oxa-11,22-diazaheptacyclo[13.9.1.01,13.02,21.04,12.05,10.019,25]pentacosa-4(12),5,7,9,15,17,19(25)-heptaene-2,16-diol;hydrochloride
• 化学式: C₂₂H₂₀N₂O₃*ClH
• 分子量: 396.873
• InChiKey: XTLNUGZGXXWUKV-ODJNVIMXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.87
• 重原子数：
  28
• 可旋转键数：
  0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  77.5
• 氢给体数：
  5
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan hydrochloride 、 alkaline earth salt of/the/ methylsulfuric acid 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 以83%的产率得到SDM25N
  参考文献：
  名称：

  Effect of N-Alkyl and N-Alkenyl Substituents in Noroxymorphindole, 17-Substituted-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7:2‘,3‘-indolomorphinans, on Opioid Receptor Affinity, Selectivity, and Efficacy

  摘要：

  The N-alkyl analogues (N-ethyl through N-heptyl), branched N-alkyl chain analogues (N-isopropyl, N-2-methylpropyl, and N-3-methylbutyl), and N-alkenyl analogues ((E)-N-3-methylallyl (crotyl), N-2-methylallyl, and N-3,3-dimethylallyl) were prepared in the noroxymorphindole series (17-substituted-6,7-dehydro-4,5 alpha -epoxy-3,12-dihydroxy-6,7:2 ' ,3 ' -indolomorphinans), and the effect of the N-substituent on opioid receptor affinity, selectivity, and efficacy was examined using receptor binding assays, [S-35]GTP gammaS efficacy determinations, and smooth muscle functional assays (electrically stimulated mouse vas deferens and guinea pig ileum). All of the compounds acted as opioid antagonists, including those with N-substituents which usually confer either weak agonist-antagonist behavior (N-ethyl) or potent opioid agonist activity (N-pentyl) in morphinan-like ligands which interact with the mu -receptor. Several N-substituted noroxymorphindoles were found to be more mu/delta -selective than naltrindole (NTI). The N-2-methylallylnoroxymorphindole, in particular, was found to be more selective than NTI in receptor binding assays (mu/delta = 1700 vs 120; kappa/delta = 810 vs 140), as an antagonist in the GTP gammaS assay (mu/delta = 170 vs 140; kappa/delta = 620 vs 160), and considerably more selective than NTI in the functional assays (mu/delta > 2200 vs 90), It also had high affinity for the delta -opioid receptor (K-i = 4.7 nM in the binding assay) and high antagonist potency (1.2 nM in the GTP gammaS assay; 8.9 nM in the MVD assay).

  DOI：

  10.1021/jm000511w
• 作为产物：
  描述：

  苯肼,盐酸盐 、 14-羟基二氢降吗啡酮盐酸盐 在 盐酸 作用下， 以 甲醇 为溶剂， 生成 6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan hydrochloride
  参考文献：
  名称：

  N-取代基对纳曲吲哚衍生物对δ阿片受体的功能活性的影响：磺胺衍生物的合成与评价

  摘要：

  我们最近报道了 N-烷基和 N-酰基纳曲吲哚 (NTI) 衍生物对 δ 阿片受体 (DOR) 表现出活性，范围广泛，从完全反向激动剂到完全激动剂。我们新设计了磺酰胺型 NTI 衍生物，以研究 N 取代基对功能活性的影响，因为与烷基胺和酰胺部分相比，磺酰胺部分的侧链和 S=O 部分位于空间不同的位置. 在测试的化合物中，环丙基磺酰胺 9f (SYK-839) 是最有效的 DOR 完全反向激动剂，而苯乙基磺酰胺 9e (SYK-901) 显示出中等效力的完全 DOR 激动剂活性。这些 NTI 衍生物有望成为研究诱导这些功能活性的分子机制的有用化合物。

  DOI：

  10.3390/molecules25173792

文献信息

• Opioid agonist and antagonist activities of morphindoles related to naltrindole
  作者：P. S. Portoghese、D. L. Larson、M. Sultana、A. E. Takemori

  DOI：10.1021/jm00101a009

  日期：1992.11

  A series of naltrindole-related ligands (4-10) with an N-methyl, N-phenethyl, N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in an antagonist state.
• Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives
  作者：Chiharu Iwamatsu、Daichi Hayakawa、Tomomi Kono、Ayaka Honjo、Saki Ishizaki、Shigeto Hirayama、Hiroaki Gouda、Hideaki Fujii

  DOI：10.3390/molecules25173792

  日期：——

  We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the N-substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially

  我们最近报道了 N-烷基和 N-酰基纳曲吲哚 (NTI) 衍生物对 δ 阿片受体 (DOR) 表现出活性，范围广泛，从完全反向激动剂到完全激动剂。我们新设计了磺酰胺型 NTI 衍生物，以研究 N 取代基对功能活性的影响，因为与烷基胺和酰胺部分相比，磺酰胺部分的侧链和 S=O 部分位于空间不同的位置. 在测试的化合物中，环丙基磺酰胺 9f (SYK-839) 是最有效的 DOR 完全反向激动剂，而苯乙基磺酰胺 9e (SYK-901) 显示出中等效力的完全 DOR 激动剂活性。这些 NTI 衍生物有望成为研究诱导这些功能活性的分子机制的有用化合物。
• Effect of <i>N</i>-Alkyl and <i>N</i>-Alkenyl Substituents in Noroxymorphindole, 17-Substituted-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7:2‘,3‘-indolomorphinans, on Opioid Receptor Affinity, Selectivity, and Efficacy
  作者：Sherita McLamore、Thomas Ullrich、Richard B. Rothman、Heng Xu、Christina Dersch、Andrew Coop、Peg Davis、Frank Porreca、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.1021/jm000511w

  日期：2001.4.1

  The N-alkyl analogues (N-ethyl through N-heptyl), branched N-alkyl chain analogues (N-isopropyl, N-2-methylpropyl, and N-3-methylbutyl), and N-alkenyl analogues ((E)-N-3-methylallyl (crotyl), N-2-methylallyl, and N-3,3-dimethylallyl) were prepared in the noroxymorphindole series (17-substituted-6,7-dehydro-4,5 alpha -epoxy-3,12-dihydroxy-6,7:2 ' ,3 ' -indolomorphinans), and the effect of the N-substituent on opioid receptor affinity, selectivity, and efficacy was examined using receptor binding assays, [S-35]GTP gammaS efficacy determinations, and smooth muscle functional assays (electrically stimulated mouse vas deferens and guinea pig ileum). All of the compounds acted as opioid antagonists, including those with N-substituents which usually confer either weak agonist-antagonist behavior (N-ethyl) or potent opioid agonist activity (N-pentyl) in morphinan-like ligands which interact with the mu -receptor. Several N-substituted noroxymorphindoles were found to be more mu/delta -selective than naltrindole (NTI). The N-2-methylallylnoroxymorphindole, in particular, was found to be more selective than NTI in receptor binding assays (mu/delta = 1700 vs 120; kappa/delta = 810 vs 140), as an antagonist in the GTP gammaS assay (mu/delta = 170 vs 140; kappa/delta = 620 vs 160), and considerably more selective than NTI in the functional assays (mu/delta > 2200 vs 90), It also had high affinity for the delta -opioid receptor (K-i = 4.7 nM in the binding assay) and high antagonist potency (1.2 nM in the GTP gammaS assay; 8.9 nM in the MVD assay).