(8aR,12aR)-8,8-dimethyl-11-methylidene-5-pentyl-2,3,4,8a,9,10,12,12a-octahydroisochromeno[3,4-h]chromene | 195866-29-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (8aR,12aR)-8,8-dimethyl-11-methylidene-5-pentyl-2,3,4,8a,9,10,12,12a-octahydroisochromeno[3,4-h]chromene
• CAS: 195866-29-6
• 化学式: C₂₄H₃₄O₂
• 分子量: 354.533
• InChiKey: HTVMMXJRLZDFOW-WOJBJXKFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  18.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (8aR,12aR)-8,8-dimethyl-11-methylidene-5-pentyl-2,3,4,8a,9,10,12,12a-octahydroisochromeno[3,4-h]chromene 在 sodium periodate 、 四氧化锇 、 potassium carbonate 、 potassium hexacyanoferrate(III) 作用下， 以 叔丁醇 为溶剂， 反应 40.0h， 生成 (8aR,12aR)-8,8-dimethyl-5-pentyl-2,3,4,8a,9,10,12,12a-octahydroisochromeno[3,4-h]chromen-11-one
  参考文献：
  名称：

  Importance of the C-1 Substituent in Classical Cannabinoids to CB₂ Receptor Selectivity:  Synthesis and Characterization of a Series of O,2-Propano-Δ⁸-tetrahydrocannabinol Analogs

  摘要：

  The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Delta(8)-tetrahydrocannabinol (O,2-propano-Delta(8)-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Delta(8)-THC, O,2-propano-Delta(9,11)-THC, O,2-propano-9-oxo-11-norhexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propane-9 alpha- and O,2-propane-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, K-i(CB1) = 90 nM, K-i(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, K-i(CB1) = 26 nm, K-i(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Delta(9,11)-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities of the O,2-propano analogs may be due to differences in salvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.

  DOI：

  10.1021/jm970136g
• 作为产物：
  描述：

  (O,2-propano-Δ⁸-THC) 在 对二甲苯 作用下， 以 异丙醇 为溶剂， 反应 16.0h， 以33%的产率得到(8aR,12aR)-8,8-dimethyl-11-methylidene-5-pentyl-2,3,4,8a,9,10,12,12a-octahydroisochromeno[3,4-h]chromene
  参考文献：
  名称：

  Importance of the C-1 Substituent in Classical Cannabinoids to CB₂ Receptor Selectivity:  Synthesis and Characterization of a Series of O,2-Propano-Δ⁸-tetrahydrocannabinol Analogs

  摘要：

  The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Delta(8)-tetrahydrocannabinol (O,2-propano-Delta(8)-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Delta(8)-THC, O,2-propano-Delta(9,11)-THC, O,2-propano-9-oxo-11-norhexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propane-9 alpha- and O,2-propane-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, K-i(CB1) = 90 nM, K-i(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, K-i(CB1) = 26 nm, K-i(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Delta(9,11)-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities of the O,2-propano analogs may be due to differences in salvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.

  DOI：

  10.1021/jm970136g