17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-5'-nitro-3,14-dihydroxyindolo[2',3':6,7]morphinan | 122431-09-8

• 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: 17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-5'-nitro-3,14-dihydroxyindolo[2',3':6,7]morphinan
• 英文别名: 5'-nitronaltrindole；(1S,2S,13R,21R)-22-(cyclopropylmethyl)-7-nitro-14-oxa-11,22-diazaheptacyclo[13.9.1.01,13.02,21.04,12.05,10.019,25]pentacosa-4(12),5(10),6,8,15,17,19(25)-heptaene-2,16-diol
• CAS: 122431-09-8
• 化学式: C₂₆H₂₅N₃O₅
• 分子量: 459.502
• InChiKey: WUUSIZOTHUJMJX-IFKAHUTRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  34
• 可旋转键数：
  2
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-5'-nitro-3,14-dihydroxyindolo[2',3':6,7]morphinan 在 N,N-二异丙基乙胺 、 mercury dichloride 、 肼 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.33h， 生成 tert-butyl (3-(E)-2-(1-((9H-fluoren-9-yl)methoxy)oxo)-3-(5'-guanidinonaltrindole)propyl)carbamate
  参考文献：
  名称：

  Investigation of Inactive-State κ Opioid Receptor Homodimerization via Single-Molecule Microscopy Using New Antagonistic Fluorescent Probes

  摘要：

  Opioid receptors (ORs) are among the best-studied G protein-coupled receptors due to their involvement in neurological disorders and important role in pain treatment. Contrary to the classical monomeric model, indirect evidence suggests that ORs might form dimers, which could be endowed with a distinct pharmacological profile, and, thus, be targeted to develop innovative pharmacological therapies. However, direct evidence for the spontaneous formation of OR dimers in living cells under physiological conditions is missing. Despite a growing interest in the. opioid receptor (KOR), KOR-selective fluorescent probes are particularly scarce in the literature. Herein, we present the first set of fluorescent KOR-selective probes with antagonistic properties. Two of these were employed in single-molecule microscopy (SMM) experiments to investigate KOR homodimerization, localization, and trafficking. Our findings indicate that most KORs labeled with the new fluorescent probes are present as apparently freely diffusing monomers on the surface of a simple cell model.

  DOI：

  10.1021/acs.jmedchem.9b02011
• 作为产物：
  描述：

  4-硝基苯肼盐酸盐 、 盐酸纳曲酮 在 盐酸 、 溶剂黄146 作用下， 以 水 为溶剂， 以59%的产率得到17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-5'-nitro-3,14-dihydroxyindolo[2',3':6,7]morphinan
  参考文献：
  名称：

  Investigation of Inactive-State κ Opioid Receptor Homodimerization via Single-Molecule Microscopy Using New Antagonistic Fluorescent Probes

  摘要：

  Opioid receptors (ORs) are among the best-studied G protein-coupled receptors due to their involvement in neurological disorders and important role in pain treatment. Contrary to the classical monomeric model, indirect evidence suggests that ORs might form dimers, which could be endowed with a distinct pharmacological profile, and, thus, be targeted to develop innovative pharmacological therapies. However, direct evidence for the spontaneous formation of OR dimers in living cells under physiological conditions is missing. Despite a growing interest in the. opioid receptor (KOR), KOR-selective fluorescent probes are particularly scarce in the literature. Herein, we present the first set of fluorescent KOR-selective probes with antagonistic properties. Two of these were employed in single-molecule microscopy (SMM) experiments to investigate KOR homodimerization, localization, and trafficking. Our findings indicate that most KORs labeled with the new fluorescent probes are present as apparently freely diffusing monomers on the surface of a simple cell model.

  DOI：

  10.1021/acs.jmedchem.9b02011

文献信息

• Potent and Selective Indolomorphinan Antagonists of the Kappa-Opioid Receptor
  作者：William C. Stevens、Robert M. Jones、Govindan Subramanian、Thomas G. Metzger、David M. Ferguson、Philip S. Portoghese

  DOI：10.1021/jm0000665

  日期：2000.7.1

  the kappa antagonist, norbinaltorphimine (1, norBNI). A variety of cationic groups were employed as a kappa address in an effort to investigate its interaction with the anionic address subsite, Glu297, on the kappa receptor. Some of the groups that were employed for this purpose were amines, amidines, guanidines, and quaternary ammonium. Members of the series were found to have a varying degree of kappa

  δ-阿片样物质拮抗剂纳曲酮（2，NTI）中的吲哚部分被用作支架，以保持与κ-阿片样物质受体相互作用的“地址”。地址与吲哚部分5'-位的连接是基于NTI在κ拮抗剂降冰片碱（1，norBNI）上的叠加。为了研究其与κ受体上的阴离子地址亚位Glu297的相互作用，采用了各种阳离子基团作为κ地址。用于该目的的一些基团是胺，am，胍和季铵。在平滑肌制剂中进行测试时，发现该系列成员具有​​不同程度的kappa拮抗剂效力和kappa选择性。5' -胍衍生物12a（GNTI）是该系列中最有效的成员，并且具有最高的κ选择性比。GNTI的效力是norBNI的2倍，选择性高6-10倍（1）。通常，该系列中效力的顺序是：胍> approximately近似为季铵>胺。κ拮抗剂效力似乎是pK（a）和配体阳离子取代基的距离限制的组合的函数。受体结合研究在质量上与药理学数据一致。对12a的分子建模研究表明，GNTI的质
• .delta. Opioid antagonist activity and binding studies of regioisomeric isothiocyanate derivatives of naltrindole: evidence for .delta. receptor subtypes
  作者：P. S. Portoghese、M. Sultana、W. L. Nelson、P. Klein、A. E. Takemori

  DOI：10.1021/jm00100a014

  日期：1992.10

  The isothiocyanate group was attached to the 4'-, 5'-, 6'-, or 7'-position of naltrindole in an effort to determine the importance of the position of this electrophilic group on the selectivity for subtypes of delta opioid receptors. All of the ligands were delta-selective when tested against standard agonists in smooth muscle preparations. However, the rank-order delta antagonism of antinociception in mice did not parallel the in vitro pharmacologic data. The 5'-isothiocyanate 2 was the most potent and selective antagonist in vivo, causing a 52-fold increase of the ED50 for [D-Ser2,D-Leu5]enkephalin-Thr6 (DSLET) and no increase for [D-Pen2,D-Pen5]enkephalin (DPDPE). The effect of each of the ligands on the binding of [H-3]DSLET and [H-3]DPDPE to guinea pig brain membranes clearly differentiated between the binding sites that recognize these radioligands. These studies provide additional evidence for the presence of two subtypes of delta opioid receptors.
• Mutational Evidence for a Common κ Antagonist Binding Pocket in the Wild-Type κ and Mutant μ[K303E] Opioid Receptors
  作者：Robert M. Jones、Siv A. Hjorth、Thue W. Schwartz、Philip S. Portoghese

  DOI：10.1021/jm9805182

  日期：1998.12.1
• Investigation of Inactive-State κ Opioid Receptor Homodimerization via Single-Molecule Microscopy Using New Antagonistic Fluorescent Probes
  作者：Antonios Drakopoulos、Zsombor Koszegi、Yann Lanoiselée、Harald Hübner、Peter Gmeiner、Davide Calebiro、Michael Decker

  DOI：10.1021/acs.jmedchem.9b02011

  日期：2020.4.9

  Opioid receptors (ORs) are among the best-studied G protein-coupled receptors due to their involvement in neurological disorders and important role in pain treatment. Contrary to the classical monomeric model, indirect evidence suggests that ORs might form dimers, which could be endowed with a distinct pharmacological profile, and, thus, be targeted to develop innovative pharmacological therapies. However, direct evidence for the spontaneous formation of OR dimers in living cells under physiological conditions is missing. Despite a growing interest in the. opioid receptor (KOR), KOR-selective fluorescent probes are particularly scarce in the literature. Herein, we present the first set of fluorescent KOR-selective probes with antagonistic properties. Two of these were employed in single-molecule microscopy (SMM) experiments to investigate KOR homodimerization, localization, and trafficking. Our findings indicate that most KORs labeled with the new fluorescent probes are present as apparently freely diffusing monomers on the surface of a simple cell model.