1-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)ethanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 1-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)ethanone
• 英文别名: 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl]ethan-1-one；1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-piperazin-1-yl]-etan-1-one；1-[4-(3-chloro-11H-benzo[b][1,4]benzodiazepin-6-yl)piperazin-1-yl]ethanone
• 化学式: C₁₉H₁₉ClN₄O
• 分子量: 354.839
• InChiKey: QMYUSAWQTCYMGK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  47.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)ethanone 在 lithium aluminum deuteride 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以84%的产率得到8-chloro-11-[4-(1,1-dideutrioethyl)piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine
  参考文献：
  名称：

  The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

  摘要：

  Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by dozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

  DOI：

  10.1021/cn500325v
• 作为产物：
  描述：

  8-氯-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮 在 N,N-二甲基苯胺 、 三乙胺 、 三氯氧磷 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 5.0h， 生成 1-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)ethanone
  参考文献：
  名称：

  The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

  摘要：

  Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by dozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

  DOI：

  10.1021/cn500325v

文献信息

• Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders
  申请人：Pettersson Lars

  公开号：US20070105836A1

  公开（公告）日：2007-05-10

  Compounds are described that are prodrugs to active compounds that modulate a muscarinic receptor. In some cases, the compounds are prodrugs to N-desmethylclozapine. The compounds may be used to treat neuropsychiatric disorders.

  描述了一些化合物，这些化合物是调节肌肉胆碱受体的活性化合物的前药。在某些情况下，这些化合物是N-去甲基氯氮平的前药。这些化合物可以用于治疗神经精神疾病。
• [EN] PRODRUGS OF MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS<br/>[FR] PROMÉDICAMENTS D'AGONISTES MUSCARINIQUES ET MÉTHODES DE TRAITEMENT DE TROUBLES NEUROPSYCHIATRIQUES
  申请人：ACADIA PHARM INC

  公开号：WO2007053618A1

  公开（公告）日：2007-05-10

  [EN] Compounds are described that are prodrugs to active compounds that modulate a muscarinic receptor. In some cases, the compounds are prodrugs to. N-desmethylclozapine. The compounds may be used to treat neuropsychiatric disorders.
  [FR] L'invention concerne des composés promédicaments de composés actifs qui modulent un récepteur muscarinique. Dans certain cas, les composés sont des promédicaments à N-desméthylclozapine. Les composés peuvent être utilisés pour traiter des troubles neuropsychiatriques.
• [EN] METHOD FOR INVESTIGATING BLOOD-BRAIN BARRIER PROPERTIES AND BRAIN METABOLISM USING INSECT BRAINS<br/>[FR] PROCÉDÉ POUR ÉTUDIER DES PROPRIÉTÉS DE BARRIÈRE HÉMATO-ENCÉPHALIQUE ET LE MÉTABOLISME DU CERVEAU À L'AIDE DE CERVEAUX D'INSECTES
  申请人：QUIXOLABS AB

  公开号：WO2016186559A1

  公开（公告）日：2016-11-24

  The present disclosure relates to a method for investigating blood-brain barrier properties and brain metabolism using an insect brain as a model system. The method comprises dissecting out an insect brain comprising the compound eyes, and exposing the brain and compound eyes to a medium comprising a chemical compound. The method allows for the investigation of various properties, including blood-brain barrier permeability of compounds, the effect agents have on the blood-brian barrier, and various aspects of brain chemistry including distribution and metabolism of agents within the brain. The method finds various uses, such as an in vitro screening model as part of drug development, or as a methodology to investigate the impact of various agents on brain chemistry and the integrity of the blood-brain barrier, both in vitro and in vivo.
• The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs
  作者：Xin Chen、Hyunah Choo、Xi-Ping Huang、Xiaobao Yang、Orrin Stone、Bryan L. Roth、Jian Jin

  DOI：10.1021/cn500325v

  日期：2015.3.18

  Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by dozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.