(8aR,11R,12aR)-8,8-dimethyl-5-pentyl-3,4,8a,9,10,11,12,12a-octahydro-2H-isochromeno[3,4-h]chromen-11-ol | 195866-37-6

• 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,11R,12aR)-8,8-dimethyl-5-pentyl-3,4,8a,9,10,11,12,12a-octahydro-2H-isochromeno[3,4-h]chromen-11-ol
• CAS: 195866-37-6
• 化学式: C₂₃H₃₄O₃
• 分子量: 358.521
• InChiKey: QXPMAJJUKZJCEC-BHIYHBOVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (8aR,11R,12aR)-8,8-dimethyl-5-pentyl-3,4,8a,9,10,11,12,12a-octahydro-2H-isochromeno[3,4-h]chromen-11-ol 在 对甲苯磺酸 作用下， 以 苯 为溶剂， 反应 4.0h， 生成 (8aR,12aR)-8,8-dimethyl-5-pentyl-3,4,8a,9,12,12a-hexahydro-2H-isochromeno[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
• 作为产物：
  描述：

  在 sodium tetrahydroborate 、 sodium periodate 作用下， 以 甲醇 、 叔丁醇 为溶剂， 反应 1.0h， 生成 (8aR,11R,12aR)-8,8-dimethyl-5-pentyl-3,4,8a,9,10,11,12,12a-octahydro-2H-isochromeno[3,4-h]chromen-11-ol
  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

文献信息

• [EN] CANNABINOID RECEPTOR INVERSE AGONISTS AND NEUTRAL ANTAGONISTS AS THERAPEUTIC AGENTS FOR THE TREATMENT OF BONE DISORDERS<br/>[FR] AGONISTES INVERSES DE RECEPTEURS DE CANNABINOIDES ET ANTAGONISTES NEUTRES AGISSANT EN TANT QU'AGENTS THERAPEUTIQUES DESTINES AU TRAITEMENT DE TROUBLES OSSEUX
  申请人：UNIV ABERDEEN

  公开号：WO2004078261A1

  公开（公告）日：2004-09-16

  The present invention pertains to cannabinoid (CB) receptor inverse agonists and neutral antagonists, and especially CB1 and CB2 inverse agonists and neutral antagonists; such as, for example, certain pyrazole compounds; their use in the inhibition of osteoclasts (for example, the inhibition of the survival, formation, and/or activity of osteoclasts), and/or in the inhibition of bone resorption; their use in connection with treatment of bone disorders, such as conditions mediated by osteoclasts (e.g., increased osteoclast activity) and/or characterised by (e.g., increased) bone resorption, such as osteoporosis (e.g., osteoporosis not associated with inflammation; e.g., osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer associated bone disease, and Paget's disease of bone.