2H-1,2-噁嗪-4,5-二醇,四氢-3-(羟甲基)-,(3R,4R,5S)-rel- | 83339-80-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 中文名称: 2H-1,2-噁嗪-4,5-二醇,四氢-3-(羟甲基)-,(3R,4R,5S)-rel-
• 英文名称: 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-6α-morphinan
• 英文别名: β-funaltrexamine；β-FNA；17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-6α-[trans-3-(methoxycarbonyl)acrylamido]morphinan；N-Methylfunaltrexamine；methyl (E)-4-[[(4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]amino]-4-oxobut-2-enoate
• CAS: 83339-80-4
• 化学式: C₂₅H₃₀N₂O₆
• 分子量: 454.523
• InChiKey: PQKHESYTSKMWFP-BEEKOEITSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6α-naltrexamine dihydrochloride 、 3-chloroformylacrylic acid methyl ester 在 3 A molecular sieve 、 三乙胺 作用下， 生成 2H-1,2-噁嗪-4,5-二醇,四氢-3-(羟甲基)-,(3R,4R,5S)-rel-
  参考文献：
  名称：

  Importance of carbon 6 chirality in conferring irreversible opioid antagonism to naltrexone-derived affinity labels

  摘要：

  A series of five epimeric pairs of naltrexone derivatives that contain an electrophilic substituent at the 6 alpha- or 6 beta-position was synthesized and tested on the guinea pig ileal longitudinal muscle (GPI) and mouse vas deferens (MVD) preparations in order to determine if the orientation of the electrophile is important for covalent bonding to opioid receptors. In the GPI all compounds were pharmacologically active as reversible agonists, but only the 6 beta-isomers of the fumaramate ester 2b (beta-FNA) and isothiocyanate 6b exhibited covalent reactivity, involving a selective irreversible antagonism of the mu agonist, morphine, without affecting kappa agonists. The 6 alpha-isomer 2a (alpha-FNA) was itself nonalkylating but was able to protect the GPI against alkylation by its epimer, beta-FNA, indicating that the two epimers bind to the same receptor. These results suggest that the proper orientation of the electrophilic substituent is required for covalent bonding with a proximal nucleophile in the case of mu receptor blockade. Moreover, the lack of covalent bonding to kappa receptors by these or other ligands in this series indicates the possible absence of sufficiently reactive nucleophiles on this recognition site. In the MVD, 2b, but not 2a, irreversibly antagonized morphine (as in GPI), whereas neither epimer exhibited irreversible antagonism toward the delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE). In contrast, both of the isothiocyanate epimers (6a,b) irreversibly blocked mu and delta receptors. Evidence suggesting differences between mu receptors in the MVD and GPI was obtained with the beta-iodoacetamide 5b, which was an irreversible blocker of morphine only in the MVD. When analyzed together with those of previous studies with the nitrogen mustard analogues, alpha- and beta-chlornaltrexamine, the data suggest that the receptor-alkylating ability of each isomer in an epimeric pair differs most when the electrophile possesses a narrow spectrum of reactivity.

  DOI：

  10.1021/jm00363a005

文献信息

• Importance of carbon 6 chirality in conferring irreversible opioid antagonism to naltrexone-derived affinity labels
  作者：L. M. Sayre、D. L. Larson、D. S. Fries、A. E. Takemori、P. S. Portoghese

  DOI：10.1021/jm00363a005

  日期：1983.9

  A series of five epimeric pairs of naltrexone derivatives that contain an electrophilic substituent at the 6 alpha- or 6 beta-position was synthesized and tested on the guinea pig ileal longitudinal muscle (GPI) and mouse vas deferens (MVD) preparations in order to determine if the orientation of the electrophile is important for covalent bonding to opioid receptors. In the GPI all compounds were pharmacologically active as reversible agonists, but only the 6 beta-isomers of the fumaramate ester 2b (beta-FNA) and isothiocyanate 6b exhibited covalent reactivity, involving a selective irreversible antagonism of the mu agonist, morphine, without affecting kappa agonists. The 6 alpha-isomer 2a (alpha-FNA) was itself nonalkylating but was able to protect the GPI against alkylation by its epimer, beta-FNA, indicating that the two epimers bind to the same receptor. These results suggest that the proper orientation of the electrophilic substituent is required for covalent bonding with a proximal nucleophile in the case of mu receptor blockade. Moreover, the lack of covalent bonding to kappa receptors by these or other ligands in this series indicates the possible absence of sufficiently reactive nucleophiles on this recognition site. In the MVD, 2b, but not 2a, irreversibly antagonized morphine (as in GPI), whereas neither epimer exhibited irreversible antagonism toward the delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE). In contrast, both of the isothiocyanate epimers (6a,b) irreversibly blocked mu and delta receptors. Evidence suggesting differences between mu receptors in the MVD and GPI was obtained with the beta-iodoacetamide 5b, which was an irreversible blocker of morphine only in the MVD. When analyzed together with those of previous studies with the nitrogen mustard analogues, alpha- and beta-chlornaltrexamine, the data suggest that the receptor-alkylating ability of each isomer in an epimeric pair differs most when the electrophile possesses a narrow spectrum of reactivity.