CLH304a | 797-17-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: CLH304a
• 英文别名: 4-<4-Hydroxy-3,5-di-tert.-butyl-phenyl>-2-oxo-buten-(3)-saeure；Pmid25050158C14；4-(3,5-ditert-butyl-4-hydroxyphenyl)-2-oxobut-3-enoic acid
• CAS: 797-17-1
• 化学式: C₁₈H₂₄O₄
• 分子量: 304.386
• InChiKey: XIQDGAUDNMVMCD-UHFFFAOYSA-N

物化性质

• 熔点：
  136-139 °C (decomp)
• 沸点：
  404.3±37.0 °C(Predicted)
• 密度：
  1.125±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  4

制备方法与用途

生物活性

GABAB 受体拮抗剂 1（化合物 14）是一种选择性的 GABAB (γ-氨基丁酸) 受体的负变构调节剂。研究显示，(E)-GABAB 受体拮抗剂 1 能降低 GABA 引起的 IP3 (三磷酸肌醇) 产生，其 IC50 值为 37.9 μM。

靶点

GABA_B

体外研究

在过表达 GABAB 受体和 Gqi9 蛋白的 HEK293 细胞中，(E)-GABAB 受体拮抗剂 1 减少了激动剂 GABA 引起的最大 IP3 生成效果，但并未改变 EC₅₀。

反应信息

• 作为反应物：
  描述：

  CLH304a 、 二甘醇胺 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 反应 12.0h， 以97 mg的产率得到
  参考文献：
  名称：

  A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits

  摘要：

  An gamma-aminobutyric acid type B (GABA(B))-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABA(B)-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABA(B)-receptor, such as antagonists, show anti-absence seizure activity and procognitive properties. In a search for allosteric compounds of the GABA(B)-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABA(B)-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABA(B)-receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABA(B)-receptor inhibition.

  DOI：

  10.1042/bj20150979
• 作为产物：
  描述：

  3,5-二叔丁基-4-羟基苯甲醛 在 三氟化硼乙醚 、 potassium carbonate 、 氯化铵 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 6.67h， 生成 CLH304a
  参考文献：
  名称：

  Discovery of a Negative Allosteric Modulator of GABA_B Receptors

  摘要：

  Initialized from the scaffold of CGP7930, an allosteric agonist of GABA(B) receptors, a series of non-competitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABA(B) receptors and Gq(j9) proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABA(B) receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABA(B) receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 mu M and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluRS. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABA(B) receptors, demonstrating that compound 14 negatively modulated GABA(B) receptors activity as a negative allosteric modulator.

  DOI：

  10.1021/ml500162z

文献信息

• A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits
  作者：B. Sun、L. Chen、L. Liu、Z. Xia、J.-P. Pin、F. Nan、J. Liu

  DOI：10.1042/bj20150979

  日期：2016.3.15

  An gamma-aminobutyric acid type B (GABA(B))-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABA(B)-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABA(B)-receptor, such as antagonists, show anti-absence seizure activity and procognitive properties. In a search for allosteric compounds of the GABA(B)-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABA(B)-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABA(B)-receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABA(B)-receptor inhibition.
• Discovery of a Negative Allosteric Modulator of GABA_B Receptors
  作者：Lin-Hai Chen、Bing Sun、Yang Zhang、Tong-Jie Xu、Zhi-Xiong Xia、Jian-Feng Liu、Fa-Jun Nan

  DOI：10.1021/ml500162z

  日期：2014.7.10

  Initialized from the scaffold of CGP7930, an allosteric agonist of GABA(B) receptors, a series of non-competitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABA(B) receptors and Gq(j9) proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABA(B) receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABA(B) receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 mu M and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluRS. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABA(B) receptors, demonstrating that compound 14 negatively modulated GABA(B) receptors activity as a negative allosteric modulator.