螺拉米特 | 510-74-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 中文名称: 螺拉米特
• 中文别名: 螺哌丙苯；螺胺
• 英文名称: Spiramide
• 英文别名: 8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one；8-[3-(4-fluorophenoxy)propyl]-4-phenyl-2,4,8-triazaspiro[4.5]decan-1-one；AMI-193；8-[3-(4-fluoro-phenoxy)-propyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one；8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one；8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
• CAS: 510-74-7
• 化学式: C₂₂H₂₆FN₃O₂
• 分子量: 383.466
• InChiKey: FJUKDAZEABGEIH-UHFFFAOYSA-N

物化性质

• 熔点：
  176 - 179°C
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  44.8
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090

制备方法与用途

生物活性

Spiramide (AMI-193) 是一种有效且选择性的 5-HT2 和 dopamine D2 受体拮抗剂，其 Ki 值分别为 2 nM 和 3 nM。与 5-HT1C 受体相比，Spiramide 对 5-HT2 受体的选择性更高（Ki = 4300 nM），约为后者选择性的 2000 多倍。该化合物具有抗精神病活性。

靶点

• 5-HT2 受体：2 nM (Ki)
• D2 受体：3 nM (Ki)
• 5-HT1A 受体：50 nM (Ki)
• D1 受体：2530 nM (Ki)
• 5-HT1C 受体：4300 nM (Ki)

体外研究

Spiramide 对 5-HT1A 受体（Ki = 50 nM）保持亲和力，同时也能与多巴胺 D2 受体结合（Ki = 3 nM），但对多巴胺 D1 受体的亲和力较低（Ki = 2530 nM）。

体内研究

• 固定间隔程序：AMI-193 在 0.003 至 0.01 mg/kg 范围内通过肌肉注射 (i.m.) 可剂量依赖性地降低恒河猴在固定间隔 (FI) 程序下的反应率。
• 药物辨别实验：AMI-193 在上述剂量范围内通过肌肉注射可减弱可卡因的刺激效应。
• 静脉自控给药程序：AMI-193 可减少恒河猴在静脉自控给药 (0.1 mg/infusion) 程序下的反应率。

动物模型

• 动物类型：成年雄性恒河猴（体重 850-1300 g）
• 剂量：0.003, 0.01 mg/kg
• 给药方式：每周一至周四肌肉注射
• 结果：减少了反应率，并且这些效果可以通过可卡因逆转。

反应信息

• 作为反应物：
  描述：

  螺拉米特 在 4-二甲氨基吡啶 、 三乙胺 、 potassium hydroxide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 3-[2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)ethyl]-8-[3-(4-fluorophenoxy)-propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one
  参考文献：
  名称：

  Target-Specific Ligands and Gadolinium-Based Complexes for Imaging of Dopamine Receptors: Synthesis, Binding Affinity, and Relaxivity

  摘要：

  Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this paper may also be useful for other imaging modalities such as PET (or SPECT) by just replacing, at the last stage of the synthesis, the gadolinium cation by other metal cations having relatively long half-lives, such as Cu-64, Zr-89, In-11, and more.

  DOI：

  10.1021/jo400646k
• 作为产物：
  描述：

  1-(3-氯丙氧基)-4-氟苯 、 1-苯基-1,3,8-三唑螺环(4,5)十烷-4-酮 在 二异丙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 以87%的产率得到螺拉米特
  参考文献：
  名称：

  Target-Specific Ligands and Gadolinium-Based Complexes for Imaging of Dopamine Receptors: Synthesis, Binding Affinity, and Relaxivity

  摘要：

  Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this paper may also be useful for other imaging modalities such as PET (or SPECT) by just replacing, at the last stage of the synthesis, the gadolinium cation by other metal cations having relatively long half-lives, such as Cu-64, Zr-89, In-11, and more.

  DOI：

  10.1021/jo400646k

文献信息

• [EN] SEROTONERGIC AGENT AND 5-HT1A-RECEPTOR ANTAGONIST<br/>[FR] AGENT SÉROTONINERGIQUE ET ANTAGONISTE DU RÉCEPTEUR 5-HT1A
  申请人：ATLAS PHARMACEUTICALS BV

  公开号：WO2021018967A1

  公开（公告）日：2021-02-04

  The present invention relates to a 5-HT1A-receptor antagonist or a derivative, precursor or metabolite thereof, in combination with at least one serotonergic agent or a derivative, precursor or metabolite thereof for use in the prevention and/or treatment of premature ejaculation, wherein the 5-HT1A-receptor antagonist or a derivative, precursor or metabolite thereof is administered separately, sequentially or simultaneously to the at least one serotonergic agent or a derivative, precursor or metabolite thereof.

  本发明涉及一种5-HT1A受体拮抗剂或其衍生物、前体或代谢物，与至少一种5-羟色胺能药物或其衍生物、前体或代谢物联合使用，用于预防和/或治疗早泄，其中5-HT1A受体拮抗剂或其衍生物、前体或代谢物分别、顺序或同时与至少一种5-羟色胺能药物或其衍生物、前体或代谢物给予。
• Diagnostic/therapeutic agents
  申请人：Klaveness Jo

  公开号：US20050002865A1

  公开（公告）日：2005-01-06

  Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said agent being capable of forming at least two types of binding pairs with a target.

  可定位的诊断和/或治疗活性剂，例如超声对比剂，包括悬浮在水载体液中的报告物，该报告物包含含气体或生成气体的材料，该剂能够与目标形成至少两种结合对。
• Ph-dependent nmda receptor antagonists
  申请人：——

  公开号：US20040138502A1

  公开（公告）日：2004-07-15

  NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, are provided as neuroprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue. Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower-than normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia tat may occur during cardiac surgery, hypoxia tat may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, chronic pain, vascular dementia and glioma tumors. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson's Alzheimer's, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers. Preferably the compounds provided herein are allosteric NMDA inhibitors.

  NMDA受体阻滞剂，包括pH敏感的NMDA受体阻滞剂，被提供作为神经保护药物，可用于中风、创伤性脑损伤、癫痫和其他涉及大脑或脊髓组织酸化的神经事件。本发明的组合物和方法用于治疗由NMDA受体激活引起的神经退行性疾病。所述化合物在具有低于正常pH的脑组织中具有增强的活性，这是由于病理条件（如中风引起的低氧血症、创伤性脑损伤、在心脏手术期间可能发生的全局缺血、呼吸停止后可能发生的低氧血症、妊娠期高血压综合症、脊髓损伤、癫痫、慢性疼痛、血管性痴呆和胶质瘤等）。所述化合物也可用于预防帕金森病、阿尔茨海默病、亨廷顿舞蹈症、肌萎缩侧索硬化症和其他已知对使用NMDA受体阻滞剂治疗有反应的神经退行性疾病患者的神经退行性。优选地，本文提供的化合物是变构NMDA抑制剂。
• PH-dependent NMDA receptor antagonists
  申请人：Traynelis Stephen F.

  公开号：US20090023791A1

  公开（公告）日：2009-01-22

  NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, are provided as neurprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue. Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower than normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia that may occur during cardiac surgery, hypoxia that may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, chrounic pain, vascular dementia and glioma rumors. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson's Alzheimer's, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers. Prefebably the compounds provided herein are allosteric NMDA inhibitors.

  NMDA受体阻滞剂，包括pH敏感的NMDA受体阻滞剂，作为神经保护药物提供，可用于中风、创伤性脑损伤、癫痫和其他涉及脑或脊髓组织酸化的神经事件。本发明的组合物和方法用于治疗由NMDA受体激活引起的神经退行性疾病。所述化合物在具有低于正常pH的脑组织中具有增强的活性，这是由于病理情况（如中风、创伤性脑损伤、可能发生于心脏手术期间的全球性缺血、呼吸停止后可能发生的低氧、先兆子痫、脊髓损伤、癫痫、慢性疼痛、血管性痴呆和胶质瘤）所致。所述化合物还可用于预防帕金森病、阿尔茨海默病、亨廷顿舞蹈症、肌萎缩侧索硬化症和其他已知对使用NMDA受体阻滞剂治疗有响应的神经退行性疾病患者的神经退行性。最好所提供的化合物是变构的NMDA抑制剂。
• Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
  申请人：Kõster Hubert

  公开号：US20100248264A1

  公开（公告）日：2010-09-30

  Capture compounds and collections thereof and methods using the compounds for the analysis of biomolecules are provided. In particular, collections, compounds and methods are provided for analyzing complex protein mixtures, such as the proteome. The compounds are multifunctional reagents that provide for the separation and isolation of complex protein mixtures. Automated systems for performing the methods also are provided.

  提供了捕获化合物及其集合以及使用这些化合物进行生物分子分析的方法。特别地，提供了用于分析复杂蛋白质混合物（如蛋白质组）的集合、化合物和方法。这些化合物是多功能试剂，可用于分离和分离复杂的蛋白质混合物。还提供了执行这些方法的自动化系统。