7-chloro-2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxoethyl]sulfanyl-3-(2-methylpropyl)quinazolin-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7-chloro-2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxoethyl]sulfanyl-3-(2-methylpropyl)quinazolin-4-one
• 化学式: C₂₃H₂₄ClN₃O₂S
• 分子量: 442.0
• InChiKey: SNIOYYCTFVOMTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  78.3
• 氢给体数：
  0
• 氢受体数：
  4

文献信息

• COMPOSITIONS AND METHODS FOR THE MODULATION OF THE CORTICOTROPIN RELEASING FACTOR BINDING PROTEIN AND THE TREATMENT OF ALCOHOL USE DISORDER
  申请人：Brown University

  公开号：US20210308107A1

  公开（公告）日：2021-10-07

  Stress responses involve corticotropin releasing factor (CRF), the two cognate receptors (CRF 1 and CRF 2 ) and the CRF-binding protein (CRFBP). Utilizing a novel cell-based assay, a C-terminal CRFBP fragment [CRFBP(10 kD)] was found to potentiates CRF-intracellular Ca 2+ release, demonstrating that CRFBP possesses excitatory roles in addition to the inhibitory role established by the N-terminal fragment of CRFBP [CRFBP(27 kD)]. This interaction was CRF 2 -specific, as CRF 1 responses were not potentiated by CRFBP(10 kD). As there were currently no small molecule ligands available that selectively interact with either CRFBP or CRF 2 , a cell-based assay was miniaturized, wherein CRFBP(10 kD) was fused as a chimera with CRF 2α , that allowed us to a perform a high-throughput screen (HTS) of approximately 350,000 small molecules. This resulted in the identification of negative allosteric modulators (NAMs) of the CRFBP(10 kD)-CRF 2 complex that blunt CRF-induced potentiation of N-Methyl-D-aspartic acid receptor (NMDAR)-mediated synaptic transmission in dopamine neurons in the ventral tegmental area (VTA). These results provide the first evidence of specific roles for CRF 2 and CRFBP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for the treatment of stress and substance abuse disorders such as alcohol use disorder.