4'-aminonaltrindone | 143619-55-0

• 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: 4'-aminonaltrindone
• 英文别名: (1S,2S,13R,21R)-6-amino-22-(cyclopropylmethyl)-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
• CAS: 143619-55-0
• 化学式: C₂₆H₂₇N₃O₃
• 分子量: 429.519
• InChiKey: FZUNRGJXFMUNKM-UAZYKBCHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  32
• 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：
  94.7
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4'-aminonaltrindone 在 三乙胺 、 mercury dichloride 作用下， 以 二氯甲烷 为溶剂， 反应 60.0h， 生成 4'-guanidino-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,14-hydroxyindolo[2',3':6,7]morphinan di(trifluoroacetic acid) salt
  参考文献：
  名称：

  Transformation of a κ-Opioid Receptor Antagonist to a κ-Agonist by Transfer of a Guanidinium Group from the 5‘- to 6‘-Position of Naltrindole

  摘要：

  The importance of the indole scaffold of GNTI 3 in directing its address (5'-guanidinium group) to associate with the Glu297 residue of the Ic-opioid receptor was investigated by the synthesis and biological evaluation of its 4'- (4a), 6'- (4b), and 7'- (4c) regioisomers. The finding that only the 5'-regioisomer (GNTI) possessed potent K-opioid antagonist activity and high affinity at K-receptors illustrates the importance of the 5'-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent K-antagonist activity. The discovery that the 6'-regioisomer of GNTI was a potent K-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6'-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the,c-receptor involves a conformational change of TM6. We propose that association of the 6'-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.

  DOI：

  10.1021/jm010095v
• 作为产物：
  描述：

  盐酸纳曲酮 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 以 甲醇 为溶剂， 115.0 ℃ 、344.73 kPa 条件下， 反应 42.5h， 生成 4'-aminonaltrindone
  参考文献：
  名称：

  .delta. Opioid antagonist activity and binding studies of regioisomeric isothiocyanate derivatives of naltrindole: evidence for .delta. receptor subtypes

  摘要：

  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.

  DOI：

  10.1021/jm00100a014

文献信息

• .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.
• Transformation of a κ-Opioid Receptor Antagonist to a κ-Agonist by Transfer of a Guanidinium Group from the 5‘- to 6‘-Position of Naltrindole
  作者：Shiv Kumar Sharma、Robert M. Jones、Thomas G. Metzger、David M. Ferguson、Philip S. Portoghese

  DOI：10.1021/jm010095v

  日期：2001.6.1

  The importance of the indole scaffold of GNTI 3 in directing its address (5'-guanidinium group) to associate with the Glu297 residue of the Ic-opioid receptor was investigated by the synthesis and biological evaluation of its 4'- (4a), 6'- (4b), and 7'- (4c) regioisomers. The finding that only the 5'-regioisomer (GNTI) possessed potent K-opioid antagonist activity and high affinity at K-receptors illustrates the importance of the 5'-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent K-antagonist activity. The discovery that the 6'-regioisomer of GNTI was a potent K-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6'-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the,c-receptor involves a conformational change of TM6. We propose that association of the 6'-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.