[3H]-LY 278584 | 109216-58-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: [3H]-LY 278584
• 英文别名: LY 278584；1-methyl-N-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1H-indazole-3-carboxamide；LY 278,584；LY-278,584；LY-278.584
• CAS: 109216-58-2
• 化学式: C₁₇H₂₂N₄O
• 分子量: 298.388
• InChiKey: DDHAJFBBJWHSBR-CLLJXQQHSA-N

物化性质

• 沸点：
  522.1±40.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于水中

计算性质

• 辛醇/水分配系数(LogP)：
  1.93
• 重原子数：
  22.0
• 可旋转键数：
  2.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  50.16
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  1-甲基-3-吲唑甲酸 在 氯化亚砜 、 三乙胺 作用下， 以 1,4-二氧六环 、 氯仿 为溶剂， 生成 [3H]-LY 278584
  参考文献：
  名称：

  吲哚为吲哚生物等排体：3-羟吲哚-3-羧酸盐的tropanyl酯和酰胺在5-羟色胺5HT3受体上的拮抗剂的合成和评价。

  摘要：

  DOI：

  10.1021/jm00392a001

文献信息

• Synthesis and Structure−Activity Relationships of Potent and Orally Active 5-HT₄ Receptor Antagonists:  Indazole and Benzimidazolone Derivatives
  作者：John M. Schaus、Dennis C. Thompson、William E. Bloomquist、Alice D. Susemichel、David O. Calligaro、Marlene L. Cohen

  DOI：10.1021/jm970857f

  日期：1998.5.1

  aminoalkylene chain led to potent 5-HT4 receptor antagonists. In particular, those systems in which the basic amine was substituted with groups capable of forming hydrogen bonds showed increased 5-HT4 receptor antagonist activity. While some of these compounds displayed high affinity for other neurotransmitter receptors (in particular, 5-HT3, alpha1, and 5-HT2A receptors), as the conformational flexibility

  合成了一系列的吲哚-3-羧酰胺，吲唑-3-羧酰胺和苯并咪唑啉酮-3-羧酰胺，并评估了对大鼠食道中5-HT4受体的拮抗剂亲和力。与相应的吲哚类似物相比，吲唑和苯并咪唑酮系列中的3-内环戊胺衍生物具有更大的5-HT4受体亲和力。通过在芳香杂环的N-1烷基化进一步提高了5-HT4受体拮抗剂的亲和力。在一系列的1-异丙基吲唑-3-羧酰胺中，用单环哌啶环系统或无环氨基亚烷基链取代双环托烷环系统导致了有效的5-HT4受体拮抗剂。特别地，其中碱性胺被能够形成氢键的基团取代的那些系统显示出增加的5-HT 4受体拮抗剂活性。尽管这些化合物中的一些对其他神经递质受体（特别是5-HT3，α1和5-HT2A受体）表现出高亲和力，但随着胺部分构象柔韧性的提高，对5-HT4受体的选择性也提高了。从这一系列化合物中，我们确定了LY353433（1-（1-甲基乙基）-N- [2- [4-[（三环[3.3.1.1（3，7）]癸-1-基羰基）氨基]
• Synthesis and biochemical evaluation of tritium-labeled 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxamide, a useful radioligand for 5HT3 receptors
  作者：David W. Robertson、William Bloomquist、Marlene L. Cohen、Leroy R. Reid、Kathryn Schenck、David T. Wong

  DOI：10.1021/jm00174a013

  日期：1990.12

  The advent of potent, highly selective 5HT3 receptor antagonists has stimulated considerable interest in 5HT3 receptor mediated physiology and pharmacology. To permit detailed biochemical studies regarding interaction of the indazole class of serotonin (5HT) antagonists with 5HT3 receptors in multiple tissues, we synthesized 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole- 3-carboxamide (LY278584, compound 9) in high specific activity, tritium-labeled form. This radioligand was selected as a synthetic target because of its potency as a 5HT3-receptor antagonist, its selectivity for this receptor viz a viz other 5HT-receptor subtypes, and the ability to readily incorporate three tritia via the indazole N-CH3 substituent. Alkylation of N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxamide (8) with sodium hydride and tritium-labeled iodomethane, followed by HPLC purification, resulted in [3H]-9 with a radiochemical purity of 99% and a specific activity of 80.5 Ci/mmol. This radioligand bound with high affinity to a single class of saturable recognition sites in membranes isolated from cerebral cortex of rat brain. The Kd was 0.69 nM and the Bmax was 16.9 fmol/mg of protein. The specific binding was excellent, and accounted for 83-93% of total binding at concentrations of 2 nM or less. The potencies of known 5HT3-receptor antagonists as inhibitors of [3H]-9 binding correlated well with their pharmacological receptor affinities as antagonists of 5HT-induced decreases in heart rate and contraction of guinea pig ileum, suggesting the central recognition site for this radioligand may be extremely similar to or identical with peripheral 5HT3 receptors.