MCL 139

• 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: MCL 139
• 英文别名: MCL-139；bis[(1R,9R,10R)-17-(cyclobutylmethyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-4-yl] butanedioate
• 化学式: C₄₆H₆₀N₂O₄
• 分子量: 704.993
• InChiKey: XZOSATCOBKLHCF-YPMSWROLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.2
• 重原子数：
  52
• 可旋转键数：
  11
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  丁二酰氯 、 butorphan 在 三乙胺 作用下， 以 氯仿 为溶剂， 反应 48.0h， 以23%的产率得到MCL 139
  参考文献：
  名称：

  Design and Synthesis of Novel Dimeric Morphinan Ligands for κ and μ Opioid Receptors

  摘要：

  A novel series of morphinans were synthesized, and their binding affinity at and functional selectivity for mu, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric morphinans, which were formed by coupling two identical morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at mu and kappa receptors (K-i = 0.09-0.2 nM at mu and K-i = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one morphinan pharmacophore and a long-chain ester group, had affinity at both mu and kappa receptors almost identical to that of the parent ligand 2. In the [S-35]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent morphinans 1 and 2 stimulated [S-35]GTPgammaS binding mediated by the mu and kappa receptors. Compounds 13 and 17 were full kappa agonists and partialy mu agonists, while compound 19 was a partial agonist at both gamma and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.

  DOI：

  10.1021/jm030139v

文献信息

• Design and Synthesis of Novel Dimeric Morphinan Ligands for κ and μ Opioid Receptors
  作者：John L. Neumeyer、Ao Zhang、Wennan Xiong、Xiao-Hui Gu、James E. Hilbert、Brian I. Knapp、S. Stevens Negus、Nancy K. Mello、Jean M. Bidlack

  DOI：10.1021/jm030139v

  日期：2003.11.1

  A novel series of morphinans were synthesized, and their binding affinity at and functional selectivity for mu, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric morphinans, which were formed by coupling two identical morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at mu and kappa receptors (K-i = 0.09-0.2 nM at mu and K-i = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one morphinan pharmacophore and a long-chain ester group, had affinity at both mu and kappa receptors almost identical to that of the parent ligand 2. In the [S-35]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent morphinans 1 and 2 stimulated [S-35]GTPgammaS binding mediated by the mu and kappa receptors. Compounds 13 and 17 were full kappa agonists and partialy mu agonists, while compound 19 was a partial agonist at both gamma and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.