2,2-dimethyllycactonic acid | 741678-54-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2,2-dimethyllycactonic acid
• 英文别名: 2-(3,3-Dimethyl-2,5-dioxopyrrolidin-1-yl)benzoic acid
• CAS: 741678-54-6
• 化学式: C₁₃H₁₃NO₄
• mdl: MFCD21506821
• 分子量: 247.251
• InChiKey: UZQIYWSTTGCFJR-UHFFFAOYSA-N

物化性质

• 熔点：
  134-136 °C
• 沸点：
  490.8±28.0 °C(Predicted)
• 密度：
  1.315±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.307
• 拓扑面积：
  74.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(3-phenylpropan-1-yl)piperidine-3-methanol 、 2,2-dimethyllycactonic acid 在 N,N'-二环己基碳二亚胺 作用下， 以85%的产率得到KAB-30
  参考文献：
  名称：

  甲基lycaconitine的E环类似物的结构活性研究。第2部分：通过对酯的修饰合成α3beta4*烟碱乙酰胆碱受体拮抗剂。

  摘要：

  用于分化神经元烟碱乙酰胆碱受体（nAChRs）的新型药物的开发对于各种病理状况的治疗很重要。为了了解nAChR *小分子相互作用的分子决定因素，我们已经制备并评估了北二萜生物碱甲基lycaconitine（MLA）的许多简单类似物。我们之前已经报道了一系列MLA的E环类似物的合成和评估。我们在这里报告了通过修饰酯来优化该系列化合物的alpha3beta4 *功能活性的信息。

  DOI：

  10.1016/j.bmcl.2004.05.001
• 作为产物：
  描述：

  2,2-二甲基琥珀酸 在 吡啶 、 乙酸酐 作用下， 以 氯仿 为溶剂， 反应 12.5h， 生成 2,2-dimethyllycactonic acid
  参考文献：
  名称：

  Synthesis, nicotinic acetylcholine receptor binding, antinociceptive and seizure properties of methyllycaconitine analogs

  摘要：

  A series of methyllycaconitine (la, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [I-125]iodo-MLA binding at rat brain alpha 7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b-f were evaluated for inhibition of binding to rat brain alpha,beta nAChR using [H-3]epibatidine. At the alpha 7 nAChR, MLA showed a K-i value of 0.87 nM, analogs 1b-e possessed Ki values of 1.67-2.16 nM, and If showed a K-i value of 26.8 nM. Surprisingly, the analog le containing the large phenyl substituent (K-i = 1.67 nM) possessed the highest affinity. None of the compounds possessed appreciable affinity for alpha,beta nAChRs. MLA antagonized nicotine-induced seizures with an AD(50) = 2 mg/kg. None of the MLA analogs were as potent as MLA in this assay. MLA and all of the MLA analogs, with the exception of 1b, antagonized nicotine's antinociceptive effects in the tail-flick assay. Compound 1c (K-i = 1.78 nM at alpha 7 nAChR) with an AD(50) value of 1.8 mg/kg was 6.7 times more potent than MLA (AD(50) = 12 mg/kg) in antagonizing nicotine's antinociceptive effects but was 5-fold less potent than MLA in blocking nicotine-induced seizures. Since MLA has been reported to show neuroprotection against beta-amyloid(1-42), these new analogs which have high alpha 7 nAChR affinity and good selectivity relative to alpha,beta nAChRs will be useful biological tools for studying the effects of alpha 7 nAChR antagonist and neuroprotection. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.10.061

文献信息

• Structure activity studies of ring E analogues of methyllycaconitine. Part 2: Synthesis of antagonists to the α3β4* nicotinic acetylcholine receptors through modifications to the ester
  作者：Stephen C Bergmeier、Khadiga A Ismail、Kristjan M Arason、Susan McKay、Darrell L Bryant、Dennis B McKay

  DOI：10.1016/j.bmcl.2004.05.001

  日期：2004.7

  number of simpler analogues of the norditerpeniod alkaloid methyllycaconitine (MLA) in an effort to understand molecular determinants of nAChR*small molecule interactions. We have previously reported the synthesis and evaluation of a series of ring E analogues of MLA. We report here the optimization of the alpha3beta4* functional activity of this series of compounds through modification of the ester.

  用于分化神经元烟碱乙酰胆碱受体（nAChRs）的新型药物的开发对于各种病理状况的治疗很重要。为了了解nAChR *小分子相互作用的分子决定因素，我们已经制备并评估了北二萜生物碱甲基lycaconitine（MLA）的许多简单类似物。我们之前已经报道了一系列MLA的E环类似物的合成和评估。我们在这里报告了通过修饰酯来优化该系列化合物的alpha3beta4 *功能活性的信息。
• Synthesis, nicotinic acetylcholine receptor binding, antinociceptive and seizure properties of methyllycaconitine analogs
  作者：F. Ivy Carroll、Wei Ma、Hernán A. Navarro、Philip Abraham、Scott A. Wolckenhauer、M.I. Damaj、Billy R. Martin

  DOI：10.1016/j.bmc.2006.10.061

  日期：2007.1

  A series of methyllycaconitine (la, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [I-125]iodo-MLA binding at rat brain alpha 7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b-f were evaluated for inhibition of binding to rat brain alpha,beta nAChR using [H-3]epibatidine. At the alpha 7 nAChR, MLA showed a K-i value of 0.87 nM, analogs 1b-e possessed Ki values of 1.67-2.16 nM, and If showed a K-i value of 26.8 nM. Surprisingly, the analog le containing the large phenyl substituent (K-i = 1.67 nM) possessed the highest affinity. None of the compounds possessed appreciable affinity for alpha,beta nAChRs. MLA antagonized nicotine-induced seizures with an AD(50) = 2 mg/kg. None of the MLA analogs were as potent as MLA in this assay. MLA and all of the MLA analogs, with the exception of 1b, antagonized nicotine's antinociceptive effects in the tail-flick assay. Compound 1c (K-i = 1.78 nM at alpha 7 nAChR) with an AD(50) value of 1.8 mg/kg was 6.7 times more potent than MLA (AD(50) = 12 mg/kg) in antagonizing nicotine's antinociceptive effects but was 5-fold less potent than MLA in blocking nicotine-induced seizures. Since MLA has been reported to show neuroprotection against beta-amyloid(1-42), these new analogs which have high alpha 7 nAChR affinity and good selectivity relative to alpha,beta nAChRs will be useful biological tools for studying the effects of alpha 7 nAChR antagonist and neuroprotection. (c) 2006 Elsevier Ltd. All rights reserved.