(D)-1-benzylpyrrolidine-2-carboxylic acid {3-[4-(2,6-dichlorophenyl)piperidine-1-yl]propyl}amide | 1028924-72-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (D)-1-benzylpyrrolidine-2-carboxylic acid {3-[4-(2,6-dichlorophenyl)piperidine-1-yl]propyl}amide
• 英文别名: 1-Benzyl-N-{3-[4-(2,6-Dichlorophenyl)piperidin-1-Yl]propyl}-D-Prolinamide；(2R)-1-benzyl-N-[3-[4-(2,6-dichlorophenyl)piperidin-1-yl]propyl]pyrrolidine-2-carboxamide
• CAS: 1028924-72-2
• 化学式: C₂₆H₃₃Cl₂N₃O
• 分子量: 474.474
• InChiKey: UWHDLFOAIARROU-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-[4-(2,6-dichlorophenyl)piperidine-1-yl]propylamine 、 N-苄基-D-脯氨酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.17h， 以65%的产率得到(D)-1-benzylpyrrolidine-2-carboxylic acid {3-[4-(2,6-dichlorophenyl)piperidine-1-yl]propyl}amide
  参考文献：
  名称：

  Structure–activity studies on the nociceptin/orphanin FQ receptor antagonist 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide

  摘要：

  Twelve derivatives of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) antagonist 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide (Comp 24) were synthesised and tested in binding experiments performed on CHOhNOP cell membranes. Among them, a novel interesting NOP receptor antagonist (compound 35) was identified by blending chemical moieties taken from different NOP receptor ligands. In vitro in various assays, Compound 35 consistently behaved as a pure, highly potent (pA(2) in the range 8.0-9.9), competitive and NOP selective antagonist. However compound 35 was found inactive when challenged against N/OFQ in vivo in the mouse tail withdrawal assay. Thus the usefulness of the novel NOP ligand compound 35 is limited to in vitro investigations. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.05.068

文献信息

• [EN] NOP RECEPTOR AGONISTS FOR THE TREATMENT OF L-DOPA INDUCED DYSKINESIAS<br/>[FR] AGONISTES DU RÉCEPTEUR DE NOP POUR LE TRAITEMENT DE DYSKINÉSIES INDUITES PAR L-DOPA
  申请人：UNIV FERRARA

  公开号：WO2008062296A2

  公开（公告）日：2008-05-29

  [EN] The present invention relates to the chronic treatment with L,3-4-dihydroxyphenylalanine (L-DOPA). Chronic L-DOPA administration still represents the most effective pharmacological therapy of Parkinson's disease (PD) although it is invariably associated with the appearance (within 5-10 years after start of the therapy, in about 80 % of patients) of motor complications that limit its clinical effectiveness and greatly reduce the quality of life of patients (Obeso et al., 2000). These motor complications encompass motor fluctuations (e.g. wearing off and "on-off fluctuations) and abnormal involuntary movements or dyskinesias (peak dose and diphasic dyskinesias, dystonia). We report for the first time that in an animal model of dyskinesias, administration of agonists at nociceptin/orphanin FQ receptors, termed NOP receptors, dramatically reduces abnormal involuntary movements induced by L-DOPA administration. NOP receptor agonists thus represent a novel class of drugs useful for the treatment of L-DOPA induced dyskinesias.
  [FR] La présente invention porte sur le traitement chronique par la L-3-4-dihydroxyphénylalanine (L-DOPA). Une administration de L-DOPA chronique représente toujours la thérapie pharmacologique la plus efficace de la maladie de Parkinson (PD), bien qu'elle soit invariablement associée à l'apparition (en l'espace de 5-10 ans après le début de la thérapie, chez environ 80 % des patients) de complications motrices qui limitent son efficacité clinique et réduisent fortement la qualité de vie des patients (Obeso et al., 2000). Ces complications motrices englobent des fluctuations motrices (par exemple, une akinésie de fin de dose et des fluctuations effet/sans effet) et des mouvements involontaires anormaux ou des dyskinésies (dose de pic et dyskinésies diphasiques, dystonie). Nous rapportons pour la première fois que, dans un modèle animal de dyskinésies, l'administration d'agonistes au niveau de récepteurs de la nociceptine/orphanine FQ, appelés les récepteurs de NOP, réduit de façon spectaculaire les mouvements involontaires anormaux induits par l'administration de L-DOPA. Les agonistes des récepteurs de NOP représentent ainsi une nouvelle classe de médicaments utiles pour le traitement de dyskinésies induites par L-DOPA.
• Structure–activity studies on the nociceptin/orphanin FQ receptor antagonist 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide
  作者：Claudio Trapella、Carmela Fischetti、Michela Pela’、Ilaria Lazzari、Remo Guerrini、Girolamo Calo’、Anna Rizzi、Valeria Camarda、David G. Lambert、John McDonald、Domenico Regoli、Severo Salvadori

  DOI：10.1016/j.bmc.2009.05.068

  日期：2009.7

  Twelve derivatives of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) antagonist 1-benzyl-N-3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide (Comp 24) were synthesised and tested in binding experiments performed on CHOhNOP cell membranes. Among them, a novel interesting NOP receptor antagonist (compound 35) was identified by blending chemical moieties taken from different NOP receptor ligands. In vitro in various assays, Compound 35 consistently behaved as a pure, highly potent (pA(2) in the range 8.0-9.9), competitive and NOP selective antagonist. However compound 35 was found inactive when challenged against N/OFQ in vivo in the mouse tail withdrawal assay. Thus the usefulness of the novel NOP ligand compound 35 is limited to in vitro investigations. (C) 2009 Elsevier Ltd. All rights reserved.