4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]cyclohexylamine | 253272-26-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]cyclohexylamine
• 英文别名: 4-(3,4-Dihydroisoquinolin-2(1H)-yl)cyclohexan-1-amine；4-(3,4-dihydro-1H-isoquinolin-2-yl)cyclohexan-1-amine
• CAS: 253272-26-3
• 化学式: C₁₅H₂₂N₂
• 分子量: 230.353
• InChiKey: RVZAGXWSLSUHRT-UHFFFAOYSA-N

物化性质

• 熔点：
  109-111 °C
• 沸点：
  351.6±42.0 °C(Predicted)
• 密度：
  1.071±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  29.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-金刚烷甲酸 、 4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]cyclohexylamine 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 6.0h， 以95%的产率得到trans-2-[4-(adamantanecarboxamido)cyclohexyl]-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  主动构象的一些芳基哌嗪突触后5-HT（1A）受体拮抗剂。

  摘要：

  已知的柔性5-HT（1A）受体配体2a-6a（K（ i）= 0.95-7 nM）具有不同的内在活性。在2b-4b（K（i）= 15-52）的情况下，在柔性配体结构中用1e，4e-二取代的环己烷环取代四亚甲基链导致5-HT（1A）受体亲和力的降低不明显nM），而衍生物5b和6b实际上是无活性的（K（i）> 1354 nM）。体内行为测试的结果表明2a和3a充当突触后5-HT（1A）受体部分激动剂。像柔性4a一样，新的刚性化合物2b-4b显示出突触后5-HT（1A）受体拮抗剂的特征。正如分子模型研究所表明的那样，由于受约束化合物的所有可能构象均属于一个大家族，因此我们已经证实了这种构象导致突触后5-HT（1A）受体阻断的假设。确定末端酰胺或限制化合物的酰亚胺和烃基探索的区域以及体外和体内研究的结果使我们能够讨论柔性配体的生物活性构象。

  DOI：

  10.1016/s0223-5234(01)01312-5
• 作为产物：
  描述：

  4-(3,4-Dihydro-1H-isoquinolin-2-yl)-cyclohexanone oxime 在 sodium 作用下， 以 正丁醇 为溶剂， 生成 4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]cyclohexylamine
  参考文献：
  名称：

  On the Bioactive Conformation of NAN-190 (1) and MP3022 (2), 5-HT_1A Receptor Antagonists

  摘要：

  Structural modifications of 1, a postsynaptic 5-HT1A receptor antagonist, provided its flexible (8, 12) and rigid (7, 9, 11, 13) analogues; Compounds 7, 8, 9, and 11 showed high 5-HT1A receptor affinity (K-i = 4-72 nM). They acted as 6-HT1A postsynaptic receptor antagonists, since, like 1, they inhibited the behavioral syndrome, i.e., flat body posture (FBP) and forepaw treading (FT), in reserpine-pretreated rats as well as the lower lip retraction (LLR) in rats, both induced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist. Compound 12, which demonstrated high 6-HT1A receptor affinity (K-i = 50 nM), revealed properties of a partial 5-HT1A receptor agonist: it induced LLR and, at the same time, inhibited FT in rats. Compound 13 (K-i = 1600 nM) was not tested in a behavioral study. Restriction of the conformational freedom in 2, a full 5-HT1A receptor antagonist, yielded compound 14 with high 5-HT1A receptor affinity (K-i = 47 nM) and partial agonist properties at postsynaptic 5-HT1A receptors in the above tests in vivo; i.e., it induced LLR and inhibited FBP and FT in rats. New constrained analogues of 1 and 2 (compounds 7 and 14, respectively) were also synthesized to recognize a bioactive conformation of those 5-HT1A receptor antagonists. On the basis of in vitro and in vivo investigations, binding and functional properties of compound 7 were found to reflect those of 1 at 5-HT1A receptors. On the other hand, compound 14, a rigid analogue of 2, showed a different activity in vivo in comparison with the parent compound. PM3 and MM calculations revealed the existence of three! low-energy conformers of 7 and six of 14, all of them belonging to the extended family of conformations. The optimized structures of both analogues had a different angle between aromatic planes of terminal fragments; moreover, the heteroaromatic system of those molecules occupied various space regions. Our present study provides support to the hypothesis that the bioactive conformation of 1, responsible for its postsynaptic 5-HT1A receptor antagonism, is an extended linear structure represented by 7.

  DOI：

  10.1021/jm991045h

文献信息

• Active conformation of some arylpiperazine postsynaptic 5-HT1A receptor antagonists
  作者：Maria Halina Paluchowska、Andrzej Jacek Bojarski、Sijka Charakchieva-Minol、Anna Wesołowska

  DOI：10.1016/s0223-5234(01)01312-5

  日期：2002.4

  The synthesis and pharmacological properties of novel conformationally restricted arylpiperazine (2b-4b) or 1,2,3,4-tetrahydroisoquinoline (5b and 6b) derivatives of the known, flexible 5-HT(1A) receptor ligands 2a-6a (K(i)=0.95-7 nM) with different intrinsic activities are reported. Replacement of a tetramethylene chain with a 1e,4e-disubstituted cyclohexane ring in the structure of flexible ligands

  已知的柔性5-HT（1A）受体配体2a-6a（K（ i）= 0.95-7 nM）具有不同的内在活性。在2b-4b（K（i）= 15-52）的情况下，在柔性配体结构中用1e，4e-二取代的环己烷环取代四亚甲基链导致5-HT（1A）受体亲和力的降低不明显nM），而衍生物5b和6b实际上是无活性的（K（i）> 1354 nM）。体内行为测试的结果表明2a和3a充当突触后5-HT（1A）受体部分激动剂。像柔性4a一样，新的刚性化合物2b-4b显示出突触后5-HT（1A）受体拮抗剂的特征。正如分子模型研究所表明的那样，由于受约束化合物的所有可能构象均属于一个大家族，因此我们已经证实了这种构象导致突触后5-HT（1A）受体阻断的假设。确定末端酰胺或限制化合物的酰亚胺和烃基探索的区域以及体外和体内研究的结果使我们能够讨论柔性配体的生物活性构象。
• On the Bioactive Conformation of NAN-190 (1) and MP3022 (2), 5-HT_1A Receptor Antagonists
  作者：Maria H. Paluchowska、Maria J. Mokrosz、Andrzej Bojarski、Anna Wesołowska、Jolanta Borycz、Sijka Charakchieva-Minol、Ewa Chojnacka-Wójcik

  DOI：10.1021/jm991045h

  日期：1999.12.2

  Structural modifications of 1, a postsynaptic 5-HT1A receptor antagonist, provided its flexible (8, 12) and rigid (7, 9, 11, 13) analogues; Compounds 7, 8, 9, and 11 showed high 5-HT1A receptor affinity (K-i = 4-72 nM). They acted as 6-HT1A postsynaptic receptor antagonists, since, like 1, they inhibited the behavioral syndrome, i.e., flat body posture (FBP) and forepaw treading (FT), in reserpine-pretreated rats as well as the lower lip retraction (LLR) in rats, both induced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist. Compound 12, which demonstrated high 6-HT1A receptor affinity (K-i = 50 nM), revealed properties of a partial 5-HT1A receptor agonist: it induced LLR and, at the same time, inhibited FT in rats. Compound 13 (K-i = 1600 nM) was not tested in a behavioral study. Restriction of the conformational freedom in 2, a full 5-HT1A receptor antagonist, yielded compound 14 with high 5-HT1A receptor affinity (K-i = 47 nM) and partial agonist properties at postsynaptic 5-HT1A receptors in the above tests in vivo; i.e., it induced LLR and inhibited FBP and FT in rats. New constrained analogues of 1 and 2 (compounds 7 and 14, respectively) were also synthesized to recognize a bioactive conformation of those 5-HT1A receptor antagonists. On the basis of in vitro and in vivo investigations, binding and functional properties of compound 7 were found to reflect those of 1 at 5-HT1A receptors. On the other hand, compound 14, a rigid analogue of 2, showed a different activity in vivo in comparison with the parent compound. PM3 and MM calculations revealed the existence of three! low-energy conformers of 7 and six of 14, all of them belonging to the extended family of conformations. The optimized structures of both analogues had a different angle between aromatic planes of terminal fragments; moreover, the heteroaromatic system of those molecules occupied various space regions. Our present study provides support to the hypothesis that the bioactive conformation of 1, responsible for its postsynaptic 5-HT1A receptor antagonism, is an extended linear structure represented by 7.