(6aR,12bS)-(+)-6-((R)-α-methoxyphenylacetyl)-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine | 177470-32-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - Dibenzazecins
• 英文名称: (6aR,12bS)-(+)-6-((R)-α-methoxyphenylacetyl)-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine
• 英文别名: (2R)-1-[(6aR,12bS)-10,11-dimethoxy-6a,7,8,12b-tetrahydro-5H-benzo[a]phenanthridin-6-yl]-2-methoxy-2-phenylethanone
• CAS: 177470-32-5
• 化学式: C₂₈H₂₉NO₄
• 分子量: 443.543
• InChiKey: ZFMSAMVXJOCXQN-XSBVVTFOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  48
• 氢给体数：
  0
• 氢受体数：
  4

上下游信息

反应信息

• 作为反应物：
  描述：

  (6aR,12bS)-(+)-6-((R)-α-methoxyphenylacetyl)-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine 在 三乙基硼氢化锂 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 生成 trans-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
• 作为产物：
  描述：

  (R)-(-)-α-甲氧基苯乙酸 在 氯化亚砜 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 (6aR,12bS)-(+)-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

• [EN] OPTICALLY ACTIVE ISOMERS OF DIHYDREXIDINE AND ITS SUBSTITUTED ANALOGS<br/>[FR] ISOMERES OPTIQUEMENT ACTIFS DE LA DIHYDREXIDINE ET DE SES ANALOGUES SUBSTITUES
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：WO1996002513A1

  公开（公告）日：1996-02-01

  (EN) Optically active hexahydrobenzo[$i(a)]phenanthridines of formula (I) wherein R is hydrogen or C1-C4 alkyl; R1 is hydrogen or a phenol protecting group, X is fluoro, chloro, bromo, iodo or a group of the formula OR5, and R2, R3, and R4 are independently selected from the group consisting of hydrogen, C1-C4alkyl, phenyl, fluoro, chloro, bromo, iodo, or a group -OR1 are disclosed. The method of resolving the racemic $i(trans)-hexahydrobenzo[a]phenanthridines into their component enantiomers is also disclosed. Pharmacological evidence reveals that only one of the enantiomers of a preferred phenanthridine, dihydrexidine, the (6a$i(R), 12b$i(S))-(+)-isomer, is active in binding to both D1-like and D2-like dopamine receptors. Various other compounds, compositions, and methods of using the optically active stereoisomers are likewise disclosed.(FR) L'invention concerne des hexahydrobenzo[$i(a)]phénanthridines optiquement actives de la formule (I). Dans cette formule, R est un hydrogène ou un C1-C4 alkyle; R1 est un hydrogène ou un groupe protecteur du phénol, X est un fluoro, un chloro, un bromo, un iodo ou un groupe de la formule OR5; R2, R3 et R4 sont choisis d'une manière indépendante dans le groupe constitué par l'hydrogène, C1-C4 alkyle, phényle, fluoro, chloro, bromo, iodo ou un groupe -OR1. On décrit également un procédé pour fractionner le mélange racémique de $i(trans)-hexahydrobenzo[$i(a)]phénanthridines en composants énantiomères. Les études pharmacologiques montrent qu'un seul des enantiomères d'une phénanthridine préférée, la dihydrexidine, en l'occurrence l'isomère (6a$i(R), 12b$i(S))-(+) se fixe activement simultanément aux récepteurs de la dopamine du type D1 et du type D2. On décrit également différents autres composés, ainsi que des compositions et des procédés d'utilisation des stéréoisomères optiquement actifs.

  （中文翻译）本发明涉及一种化合物，即式（I）中的光学活性六氢苯并[$i(a)]菲啶，其中R是氢或C1-C4烷基；R1是氢或苯酚保护基；X是氟、氯、溴、碘或式OR5的基团，而R2、R3和R4是独立地从羟基、C1-C4烷基、苯基、氟、氯、溴、碘或基团-OR1中选择的。本发明还公开了将外消旋的$i(trans)-六氢苯并[$i(a)]菲啶分离成其组分对映异构体的方法。药理学证据表明，优选的菲啶二氢雷克西定的两个对映异构体中，只有一个（6a$i(R), 12b$i(S))-(+)-异构体对D1型和D2型多巴胺受体都具有结合活性。本发明还公开了各种其他化合物、组合物和使用光学活性对映异构体的方法。
• OPTICALLY ACTIVE ISOMERS OF DIHYDREXIDINE AND ITS SUBSTITUTED ANALOGS
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：EP0773933A1

  公开（公告）日：1997-05-21