10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine
• 英文别名: 10,11-Dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine
• 化学式: C₁₉H₂₁NO₂
• 分子量: 295.381
• InChiKey: OHIPNEPFZFYAFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  30.5
• 氢给体数：
  1
• 氢受体数：
  3

上下游信息

反应信息

• 作为反应物：
  描述：

  (R)-(-)-α-methoxyphenylacetyl chloride 、 10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine 以 二氯甲烷 、 水 为溶剂， 以24%的产率得到(6aS,12bR)-(-)-6-((R)-α-methoxyphenylacetyl)-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine
  参考文献：
  名称：

  Dopaminergic Benzo[a]phenanthridines: Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist

  摘要：

  Racemic trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D-1 dopamine receptor. In addition to its full D-1 agonist properties, 2 also is a good ligand for D-2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D-1 and D-2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D-1 receptor labeled by [H-3]SCH23390 (K(0.5)s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D-1 receptors expressed in transfected Ltk(-) cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC(50) of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 mu M for the (-)-enantiomer. With respect to D-2-like receptors, (+)-2 had a K-0.5 of 87.7 nM in competing with [H-3]spiperone at D-2 binding sites in rat striatal membranes versus about 1 mu M for the (-)-enantiomer. Together, these data demonstrate that both the D-1 and D-2 activities of dihydrexidine reside principally in the (GaR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D-1 receptor.

  DOI：

  10.1021/jm00041a025

文献信息

• Dopaminergic Benzo[a]phenanthridines: Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist
  作者：Timm A. Knoerzer、David E. Nichols、William K. Brewster、Val J. Watts、David Mottola、Richard B. Mailman

  DOI：10.1021/jm00041a025

  日期：1994.7

  Racemic trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D-1 dopamine receptor. In addition to its full D-1 agonist properties, 2 also is a good ligand for D-2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D-1 and D-2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D-1 receptor labeled by [H-3]SCH23390 (K(0.5)s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D-1 receptors expressed in transfected Ltk(-) cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC(50) of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 mu M for the (-)-enantiomer. With respect to D-2-like receptors, (+)-2 had a K-0.5 of 87.7 nM in competing with [H-3]spiperone at D-2 binding sites in rat striatal membranes versus about 1 mu M for the (-)-enantiomer. Together, these data demonstrate that both the D-1 and D-2 activities of dihydrexidine reside principally in the (GaR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D-1 receptor.