1-(3'-oxo-1'-cyclopentenyl)-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine | 205999-80-0

• 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: 1-(3'-oxo-1'-cyclopentenyl)-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine
• 英文别名: 3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]cyclopent-2-en-1-one
• CAS: 205999-80-0
• 化学式: C₁₈H₂₃NO₂
• 分子量: 285.386
• InChiKey: ZKGSKKBRSICMAU-SCLBCKFNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(3'-oxo-1'-cyclopentenyl)-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine 在 platinum(IV) oxide 氢气 、 乙酰氯 作用下， 以 甲醇 为溶剂， 反应 48.0h， 以83%的产率得到(+)-N-cyclopentyl-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine
  参考文献：
  名称：

  Investigation of the N-Substituent Conformation Governing Potency and μ Receptor Subtype-Selectivity in (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)- piperidine Opioid Antagonists

  摘要：

  A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [S-35]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.

  DOI：

  10.1021/jm980063g
• 作为产物：
  描述：

  1,3-环戊二酮 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 14.0h， 生成 1-(3'-oxo-1'-cyclopentenyl)-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine
  参考文献：
  名称：

  Investigation of the N-Substituent Conformation Governing Potency and μ Receptor Subtype-Selectivity in (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)- piperidine Opioid Antagonists

  摘要：

  A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [S-35]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.

  DOI：

  10.1021/jm980063g

文献信息

• Investigation of the N-Substituent Conformation Governing Potency and μ Receptor Subtype-Selectivity in (+)-(3<i>R</i>,4<i>R</i>)-Dimethyl-4-(3-hydroxyphenyl)- piperidine Opioid Antagonists
  作者：James B. Thomas、S. Wayne Mascarella、Richard B. Rothman、John S. Partilla、Heng Xu、Karen B. McCullough、Christina M. Dersch、Buddy E. Cantrell、Dennis M. Zimmerman、F. Ivy Carroll

  DOI：10.1021/jm980063g

  日期：1998.5.1

  A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [S-35]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.