5'-N'-(N'',N'''-bis(benzyloxycarbonyl)guanidino)-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,14-hydroxyindolo[2',3':6,7]morphinan | 350799-70-1

• 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: 5'-N'-(N'',N'''-bis(benzyloxycarbonyl)guanidino)-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,14-hydroxyindolo[2',3':6,7]morphinan
• 英文别名: benzyl N-[N'-[(1S,2S,13R,21R)-22-(cyclopropylmethyl)-2,16-dihydroxy-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)-heptaen-7-yl]-N-phenylmethoxycarbonylcarbamimidoyl]carbamate
• CAS: 350799-70-1
• 化学式: C₄₃H₄₁N₅O₇
• 分子量: 739.828
• InChiKey: UCMRVSSBVOEPEW-DSQHSLRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  55
• 可旋转键数：
  11
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  158
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5'-N'-(N'',N'''-bis(benzyloxycarbonyl)guanidino)-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,14-hydroxyindolo[2',3':6,7]morphinan 在 10percent Pd/C 盐酸 、 氢气 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以90%的产率得到5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3,14-dihydroxy-6,7-3',3'-indolomorphinan dihydrochloride
  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：

  1,3-二(苄氧羰基)-2-甲基异硫脲 、 5'-amino-17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-3,14-dihydroxyindolo[2',3':6,7]morphinan 在 三乙胺 、 mercury dichloride 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以78%的产率得到5'-N'-(N'',N'''-bis(benzyloxycarbonyl)guanidino)-17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,14-hydroxyindolo[2',3':6,7]morphinan
  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

文献信息

• 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.