(R)-(-)-3-(N-methylpyrrolidin-2-ylcarbonyl)-5-methoxyindole | 250672-54-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (R)-(-)-3-(N-methylpyrrolidin-2-ylcarbonyl)-5-methoxyindole
• 英文别名: 5-methoxy-3-[(2R)-1-methylpyrrolidine-2-carbonyl]-1H-indole；(5-methoxy-1H-indol-3-yl)-[(2R)-1-methylpyrrolidin-2-yl]methanone
• CAS: 250672-54-9
• 化学式: C₁₅H₁₈N₂O₂
• 分子量: 258.32
• InChiKey: PIDKOVWQCFASGM-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  45.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-(-)-3-(N-methylpyrrolidin-2-ylcarbonyl)-5-methoxyindole 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以95%的产率得到(R)-5-Methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole
  参考文献：
  名称：

  Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain

  摘要：

  The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach was developed that had certain advantages over the synthesis originally reported for the isomers of 1. (+)-3-(N-Methylpyrrolidin-3-yl)-4-hydroxyindole, 5, was also prepared as a rigid analogue of psilocin and compared with its 5-methoxy counterpart 4. Radioligand competition assays were used to assess the affinity of compounds for the 5-HT2A receptor labeled with the agonist ligand [I-125]DOI and the antagonist ligand [H-3]MDL100907. Two-lever drug discrimination assays in rats trained to discriminate either LSD or DOI from saline were employed to assess the hallucinogen-like behavioral properties of these rigid tryptamine analogues. The receptor binding assay results clearly demonstrated a stereochemical preference for the R enantiomers that did not discriminate the position of the oxygen function. The receptor is 10-20-fold more selective for the R isomers. The affinities of the R enantiomers were virtually identical for both 1 and 3 at the agonist-labeled receptor, while racemic 4 and 5 had about one-tenth the affinity. The drug discrimination data in both LSD- and DOI-trained rats paralleled the binding data using [I-125]DOI displacement. Both (R)-1 and (R)-3 are about equipotent, comparable to DOI in activity but about 10-fold less potent than LSD. Compound 4 produced only partial substitution, even at a dose nearly 5-fold higher than for (R)-1. Based on conformational energies, it seems doubtful that these compounds bind to the 5-HT2A receptor in an ergoline-like conformation. The results also suggest that both 1 and 3 would possess LSD-like psychopharmacology in humans.

  DOI：

  10.1021/jm990325u
• 作为产物：
  描述：

  1-(tert-Butyldimethylsilyl)-5-methoxyindole 在 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 12.5h， 生成 (R)-(-)-3-(N-methylpyrrolidin-2-ylcarbonyl)-5-methoxyindole
  参考文献：
  名称：

  Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain

  摘要：

  The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach was developed that had certain advantages over the synthesis originally reported for the isomers of 1. (+)-3-(N-Methylpyrrolidin-3-yl)-4-hydroxyindole, 5, was also prepared as a rigid analogue of psilocin and compared with its 5-methoxy counterpart 4. Radioligand competition assays were used to assess the affinity of compounds for the 5-HT2A receptor labeled with the agonist ligand [I-125]DOI and the antagonist ligand [H-3]MDL100907. Two-lever drug discrimination assays in rats trained to discriminate either LSD or DOI from saline were employed to assess the hallucinogen-like behavioral properties of these rigid tryptamine analogues. The receptor binding assay results clearly demonstrated a stereochemical preference for the R enantiomers that did not discriminate the position of the oxygen function. The receptor is 10-20-fold more selective for the R isomers. The affinities of the R enantiomers were virtually identical for both 1 and 3 at the agonist-labeled receptor, while racemic 4 and 5 had about one-tenth the affinity. The drug discrimination data in both LSD- and DOI-trained rats paralleled the binding data using [I-125]DOI displacement. Both (R)-1 and (R)-3 are about equipotent, comparable to DOI in activity but about 10-fold less potent than LSD. Compound 4 produced only partial substitution, even at a dose nearly 5-fold higher than for (R)-1. Based on conformational energies, it seems doubtful that these compounds bind to the 5-HT2A receptor in an ergoline-like conformation. The results also suggest that both 1 and 3 would possess LSD-like psychopharmacology in humans.

  DOI：

  10.1021/jm990325u

文献信息

• [EN] INDOLE DERIVATIVES AS SEROTONERGIC AGENTS USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] DÉRIVÉS D'INDOLE EN TANT QU'AGENTS SÉROTONINERGIQUES UTILES POUR LE TRAITEMENT DE TROUBLES ASSOCIÉS À CEUX-CI
  申请人：MINDSET PHARMA INC

  公开号：WO2022183288A1

  公开（公告）日：2022-09-09

  The present application relates to 3-amino-indole derivatives of general Formula (I-B), to processes for their preparation, to compositions comprising them and to their use in activation of a serotonin receptors in a cell, as well as to treating diseases, disorders or conditions by activation of a serotonin receptors in a cell. The diseases, disorders or conditions include, for example, psychosis, mental illnesses and CNS disorders. Formula (I-B)

  本申请涉及到一般式(I-B)的3-氨基吲哚衍生物，涉及其制备过程、包含它们的组合物以及它们在细胞中激活5-羟色胺受体的应用，以及通过激活细胞中的5-羟色胺受体来治疗疾病、障碍或病况。这些疾病、障碍或病况包括精神病、精神疾病和中枢神经系统障碍。式(I-B)如下：
• Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain
  作者：Madina Gerasimov、Danuta Marona-Lewicka、Deborah M. Kurrasch-Orbaugh、Amjad M. Qandil、David E. Nichols

  DOI：10.1021/jm990325u

  日期：1999.10.1

  The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach was developed that had certain advantages over the synthesis originally reported for the isomers of 1. (+)-3-(N-Methylpyrrolidin-3-yl)-4-hydroxyindole, 5, was also prepared as a rigid analogue of psilocin and compared with its 5-methoxy counterpart 4. Radioligand competition assays were used to assess the affinity of compounds for the 5-HT2A receptor labeled with the agonist ligand [I-125]DOI and the antagonist ligand [H-3]MDL100907. Two-lever drug discrimination assays in rats trained to discriminate either LSD or DOI from saline were employed to assess the hallucinogen-like behavioral properties of these rigid tryptamine analogues. The receptor binding assay results clearly demonstrated a stereochemical preference for the R enantiomers that did not discriminate the position of the oxygen function. The receptor is 10-20-fold more selective for the R isomers. The affinities of the R enantiomers were virtually identical for both 1 and 3 at the agonist-labeled receptor, while racemic 4 and 5 had about one-tenth the affinity. The drug discrimination data in both LSD- and DOI-trained rats paralleled the binding data using [I-125]DOI displacement. Both (R)-1 and (R)-3 are about equipotent, comparable to DOI in activity but about 10-fold less potent than LSD. Compound 4 produced only partial substitution, even at a dose nearly 5-fold higher than for (R)-1. Based on conformational energies, it seems doubtful that these compounds bind to the 5-HT2A receptor in an ergoline-like conformation. The results also suggest that both 1 and 3 would possess LSD-like psychopharmacology in humans.