5'-(2-chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxypyrido[2',3':6,7]morphinan

• 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'-(2-chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxypyrido[2',3':6,7]morphinan
• 英文别名: (1S,2S,10R,18R)-6-(2-chlorophenyl)-19-(cyclopropylmethyl)-11-oxa-8,19-diazahexacyclo[10.9.1.01,10.02,18.04,9.016,22]docosa-4(9),5,7,12,14,16(22)-hexaene-2,13-diol
• 化学式: C₂₉H₂₇ClN₂O₃
• 分子量: 486.998
• InChiKey: UPLRMEJLQIZHCN-FQYQUSJJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  65.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  纳曲酮 、 2-(2-chlorophenyl)-3-(dimethylamino)-2-propenal 在 乙酸铵 、 溶剂黄146 作用下， 反应 20.0h， 以29%的产率得到5'-(2-chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxypyrido[2',3':6,7]morphinan
  参考文献：
  名称：

  Novel ligands for the opioid receptors: synthesis and structure–activity relationships among 5′-aryl and 5′-heteroaryl 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinans

  摘要：

  A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5'-position of the pyridine ring of 17-cyclopropylmethyl-4,5alpha-epoxypyrido[2,3:6,7]morphinan was synthesized and evaluated for binding and functional activity at the opioid delta, mu, and kappa receptors. All of these pyridomorphinans bound with higher affinity at the delta site than at mu or kappa sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (101), 2-nitrophenyl (10n), 2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the delta receptor with subnanomolar affinity. Compound 10c with the p-tolyl substituent displayed the highest mu/delta selectivity (ratio = 42) whereas compound 101 with the 2-chlorophenyl substituent displayed the highest kappa/delta selectivity (ratio 23). At 10 muM concentration, the in vitro functional activity determined using [S-35]GTP-gamma-S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the delta, mu, and kappa receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent 6 selective antagonist. In the [S-35]GTP-7-S assays this compound had a functional antagonist K-i value of 0.2, 4.52, and 7.62 nM at the delta, mu, and kappa receptors, respectively. In the smooth muscle assays 10c displayed delta antagonist potency with a K-e value of 0.88 nM. As an antagonist, it was 70-fold more potent at the 6 receptors in the MVD than at the mu receptors in the GPI. The in vitro delta antagonist profile of this pyridomorphinan 10c resembles that of the widely used delta selective antagonist ligand naltrindole. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00432-2

文献信息

• Novel ligands for the opioid receptors: synthesis and structure–activity relationships among 5′-aryl and 5′-heteroaryl 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinans
  作者：Subramaniam Ananthan、Naveen K Khare、Surendra K Saini、Peg Davis、Christina M Dersch、Frank Porreca、Richard B Rothman

  DOI：10.1016/s0968-0896(03)00432-2

  日期：2003.9

  A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5'-position of the pyridine ring of 17-cyclopropylmethyl-4,5alpha-epoxypyrido[2,3:6,7]morphinan was synthesized and evaluated for binding and functional activity at the opioid delta, mu, and kappa receptors. All of these pyridomorphinans bound with higher affinity at the delta site than at mu or kappa sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (101), 2-nitrophenyl (10n), 2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the delta receptor with subnanomolar affinity. Compound 10c with the p-tolyl substituent displayed the highest mu/delta selectivity (ratio = 42) whereas compound 101 with the 2-chlorophenyl substituent displayed the highest kappa/delta selectivity (ratio 23). At 10 muM concentration, the in vitro functional activity determined using [S-35]GTP-gamma-S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the delta, mu, and kappa receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent 6 selective antagonist. In the [S-35]GTP-7-S assays this compound had a functional antagonist K-i value of 0.2, 4.52, and 7.62 nM at the delta, mu, and kappa receptors, respectively. In the smooth muscle assays 10c displayed delta antagonist potency with a K-e value of 0.88 nM. As an antagonist, it was 70-fold more potent at the 6 receptors in the MVD than at the mu receptors in the GPI. The in vitro delta antagonist profile of this pyridomorphinan 10c resembles that of the widely used delta selective antagonist ligand naltrindole. (C) 2003 Elsevier Ltd. All rights reserved.