beta-富纳曲胺 | 72782-05-9

• 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: beta-富纳曲胺
• 中文别名: (11Z,13E)-7,16-二乙基-4,6-二羟基-5,9,13,15-四甲基氧杂环十六碳-11,13-二烯-2,10-二酮
• 英文名称: beta-funaltrexamine
• 英文别名: β-funaltrexamine；β-FNA；methyl (E)-4-[[(4R,4aS,7R,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: 72782-05-9
• 化学式: C₂₅H₃₀N₂O₆
• 分子量: 454.523
• InChiKey: PQKHESYTSKMWFP-WZJCLRDWSA-N

物化性质

• 沸点：
  695.2±55.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)

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：

  6β-naltrexamine hydrochloride 、 3-chloroformylacrylic acid methyl ester 在 3 A molecular sieve 、 三乙胺 作用下， 生成 beta-富纳曲胺
  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

• Potential Irreversible Ligands for Opioid Receptors. Cinnamoyl Derivatives of β-Naltrexamine
  作者：Ian Derrick、John W Lewis、Humphrey A Moynihan、Jillian Broadbear、James H Woods

  DOI：10.1111/j.2042-7158.1996.tb07121.x

  日期：2011.4.12

  Cinnamoyl derivatives of β-naltrexamine (β-NTA) have been prepared and evaluated as potential irreversible opioid antagonists.

  In receptor binding assays, isolated tissue preparations and mouse antinociception assays the p-methylcinnamoyl derivative BU42 was similar to the standard opioid ligand β-funaltrexamine (β-FNA). The main features were reversible κ agonism and irreversible μ antagonism. Surprisingly the p-chlorocinnamoyl derivative BU59 showed only modest competitive antagonist activity in-vivo despite appearing to bind irreversibly to μ receptors in the guinea-pig ileum (GPI) preparation. BU60, the dihydrocinnamoyl analogue of BU59, like BU59 displayed reversible κ agonism in GPI but in mouse antinociception assays its agonism was mediated by κ and β receptors rather than κ.

  The surprising changes of profile attributable to substitution in the aromatic ring of the cinnamoylamido group in this small series suggests that a larger range of substituted cinnamoylamido derivatives should be studied to further elucidate the effects of Michael acceptor activity and other factors.

  已制备并评估了β-纳曲酰胺（β-NTA）的肉桂酰衍生物作为潜在的不可逆阿片受体拮抗剂。

  在受体结合实验、分离组织制剂和小鼠抗痛觉实验中，对p-甲基肉桂酰衍生物BU42进行评估，发现其与标准阿片受体配体β-呋纳曲酰胺（β-FNA）相似。其主要特征是可逆的κ激动作用和不可逆的μ拮抗作用。令人惊讶的是，对p-氯肉桂酰衍生物BU59进行评估发现，尽管在豚鼠肠（GPI）制剂中似乎与μ受体不可逆结合，但在体内仅表现出适度的竞争性拮抗活性。类似于BU59的二氢肉桂酰类似物BU60，在GPI中显示出可逆的κ激动作用，但在小鼠抗痛觉实验中，其激动作用是通过κ和β受体介导的，而不是仅通过κ受体。

  在这个小系列中，由于对肉桂酰胺基芳香环的取代引起的特征变化，建议研究更多取代肉桂酰胺衍生物以进一步阐明Michael受体活性和其他因素的影响。

• 4-FLUORO-4-ARYLPIPERDIN-1-YL DERIVATIVES AS MU OPIOID FUNCTION MODERATORS
  申请人：Fairfax David J.

  公开号：US20130045165A1

  公开（公告）日：2013-02-21

  4-Fluoro-4-phenylpiperidin- 1 -yl μ antagonists of general structure as well as pharmaceutical compositions comprising compounds of formula I, are disclosed. These compounds and compositions are useful as treatments of conditions or diseases associated with binding opioid receptors including pain, obesity, hyperalgesia, inflammation, osteoarthritis, drug addiction, and cancer. These compounds and compositions are also useful as treatments for tardive dyskinesia.

  本发明涉及一种通用结构的4-氟-4-苯基哌啶-1-基μ拮抗剂，以及包含式I化合物的制药组合物。这些化合物和组合物可用于治疗与结合阿片受体有关的疾病或症状，包括疼痛、肥胖症、高痛敏性、炎症、骨关节炎、药物成瘾和癌症。这些化合物和组合物还可用于治疗迟发性运动障碍。
• QUATERNARY OPIOID CARBOXAMIDES
  申请人：Wentland Mark P.

  公开号：US20090197905A1

  公开（公告）日：2009-08-06

  Compounds of formulas: are disclosed. The compounds are useful for ameliorating the side effects of therapeutic opiates.

  公式为：的化合物被揭示。这些化合物对于改善治疗鸦片类药物的副作用是有用的。
• Methods and compositions to prevent addiction
  申请人：FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION, INC.

  公开号：US11045465B2

  公开（公告）日：2021-06-29

  Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject comprising, administering a therapeutic amount of the neurological stimulant and administering an antagonist of the kappa opioid receptor, to thereby reduce or prevent the development of aversion to the CNS stimulant in the subject. Also disclosed is a method of reducing or preventing the development of addiction to a CNS stimulant in a subject, comprising, administering the CNS stimulant and administering a mu opioid receptor antagonist to thereby reduce or prevent the development of addiction to the CNS stimulant in the subject. Also disclosed are pharmaceutical compositions comprising a central nervous system stimulant and an opioid receptor antagonist. Examples of central nervous system stimulants (such as methylphenidate) and opioid receptor antagonists (such as naltrexone) are provided.

  本文公开了一种减少或防止受试者对中枢神经系统兴奋剂产生厌恶感的方法，包括施用治疗量的神经兴奋剂和施用卡巴阿片受体拮抗剂，从而减少或防止受试者对中枢神经系统兴奋剂产生厌恶感。还公开了一种减少或防止受试者对中枢神经刺激物成瘾的方法，包括施用中枢神经刺激物和施用μ阿片受体拮抗剂，从而减少或防止受试者对中枢神经刺激物成瘾。还公开了包含中枢神经系统兴奋剂和阿片受体拮抗剂的药物组合物。提供了中枢神经系统兴奋剂（如哌醋甲酯）和阿片受体拮抗剂（如纳曲酮）的实例。
• A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities
  作者：Philip S. Portoghese、Dennis L. Larson、Lawrence M. Sayre、David S. Fries、A. E. Takemori

  DOI：10.1021/jm00177a002

  日期：1980.3