(1R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-thione | 444882-98-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (1R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-thione
• 英文别名: (-)-12-acetylthiocytisine；1-[(1R,5S)-1,5,6,8-Tetrahydro-8-thioxo-1,5-methano-2H-pyrido[1,2-a][1,5]diazocin-3(4H)-yl]ethanone；1-[(1R,9S)-6-sulfanylidene-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-11-yl]ethanone
• CAS: 444882-98-8
• 化学式: C₁₃H₁₆N₂OS
• 分子量: 248.349
• InChiKey: NSVGJYPFMJDKSV-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  cytisine 在 劳森试剂 、 4-二甲氨基吡啶 、 sodium carbonate 作用下， 以 二氯甲烷 为溶剂， 反应 16.05h， 生成 (1R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-thione
  参考文献：
  名称：

  Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands

  摘要：

  We have developed one-step syntheses of halogenated derivatives of (-)-cytisine featuring a halogen substituent at positions 3, 5 or 3 and 5 of the 2-pyridone fragment, and prepared the novel bioisosteric thiocytisine by oxygen-sulphur exchange. The affinities of these pyridone-modified analogs of (-)-cytisine for (alpha (4))(2)(beta (2)),(3) and alpha7* nAChRs in rat forebrain membranes were determined by competition with (+/-)-[H-3]epibatidine and [H-3]MLA, respectively. The 3-halocytisines 7 possess subnanomolar affinities for (alpha4)(2)(beta2)(3) nAChRs, higher than those found for (-)-cytisine as well as for the 5-halocytisines 8 and 3,5-dihalocytisines 6. In contrast to the parent alkaloid the 3-halogenated species display much a higher affinity for the alpha7* nAChR subtype. The most potent molecule was 3-bromocytisine (7b) with preferential selectivity (200-fold) for the (alpha4)(2)(beta2)(3) subtype [K-i = 10 pM (alpha4 beta2) and 2.0 nM (alpha7*)]. Replacement of the lactam with a thiolactam pharmacophore to thiocytisine (12) resulted in a subnanomolar affinity for the (alpha4)(2)(beta2)(3) nAChR subtype (K-i = 0.832 nM), but in a drastic decrease of affinity for the alpha7* subtype; thiocytisine (12) has a K-i value of 4000 nM (alpha7*), giving a selectivity of 4800-fold for the neuronal (alpha4)(2)(beta2)(3)-nAChR and thus displaying the best affinity-selectivity profile in the series under consideration. (C) 2001 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(01)01222-3

文献信息

• Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands
  作者：P Imming

  DOI：10.1016/s0223-5234(01)01222-3

  日期：2001.4

  We have developed one-step syntheses of halogenated derivatives of (-)-cytisine featuring a halogen substituent at positions 3, 5 or 3 and 5 of the 2-pyridone fragment, and prepared the novel bioisosteric thiocytisine by oxygen-sulphur exchange. The affinities of these pyridone-modified analogs of (-)-cytisine for (alpha (4))(2)(beta (2)),(3) and alpha7* nAChRs in rat forebrain membranes were determined by competition with (+/-)-[H-3]epibatidine and [H-3]MLA, respectively. The 3-halocytisines 7 possess subnanomolar affinities for (alpha4)(2)(beta2)(3) nAChRs, higher than those found for (-)-cytisine as well as for the 5-halocytisines 8 and 3,5-dihalocytisines 6. In contrast to the parent alkaloid the 3-halogenated species display much a higher affinity for the alpha7* nAChR subtype. The most potent molecule was 3-bromocytisine (7b) with preferential selectivity (200-fold) for the (alpha4)(2)(beta2)(3) subtype [K-i = 10 pM (alpha4 beta2) and 2.0 nM (alpha7*)]. Replacement of the lactam with a thiolactam pharmacophore to thiocytisine (12) resulted in a subnanomolar affinity for the (alpha4)(2)(beta2)(3) nAChR subtype (K-i = 0.832 nM), but in a drastic decrease of affinity for the alpha7* subtype; thiocytisine (12) has a K-i value of 4000 nM (alpha7*), giving a selectivity of 4800-fold for the neuronal (alpha4)(2)(beta2)(3)-nAChR and thus displaying the best affinity-selectivity profile in the series under consideration. (C) 2001 Editions scientifiques et medicales Elsevier SAS.