6α-naltrexamine dihydrochloride | 63463-06-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: 6α-naltrexamine dihydrochloride
• 英文别名: alpha-Naltrexamine dihydrochloride；(4R,4aS,7S,7aR,12bS)-7-amino-3-(cyclopropylmethyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;hydrochloride
• CAS: 63463-06-9
• 化学式: C₂₀H₂₆N₂O₃*2ClH
• 分子量: 415.36
• InChiKey: RWHNEYGKXXZAGD-AWGDMYCFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.71
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  79
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6α-naltrexamine dihydrochloride 在 3 A molecular sieve 、 caesium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 10.0h， 生成 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-6β-morphinan
  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
• 作为产物：
  描述：

  盐酸纳曲酮 在 palladium on activated charcoal 盐酸 、 氢气 、 对甲苯磺酸 作用下， 以 甲醇 、 苯 为溶剂， 反应 154.0h， 生成 6α-naltrexamine dihydrochloride
  参考文献：
  名称：

  Stereospecific synthesis of the 6.alpha.- and 6.beta.-amino derivatives of naltrexone and oxymorphone

  摘要：

  DOI：

  10.1021/jo01304a051

文献信息

• [EN] POTENT AND SELECTIVE MU OPIOID RECEPTOR MODULATORS<br/>[FR] MODULATEURS PUISSANTS ET SÉLECTIFS DES RÉCEPTEURS OPIOÏDES MU
  申请人：UNIV VIRGINIA COMMONWEALTH

  公开号：WO2017200970A1

  公开（公告）日：2017-11-23

  Analogues of 6 α/β-naltrexamine (NAQ) are provided. The analogues are selective, reversible antagonists of the mu opioid receptor (MOR) that exhibit good blood brain barrier penetration. The compounds are used in the treatment of opioid addiction and other diseases and conditions, including for the treatment of pain.

  提供了6个α/β-纳曲酮胺（NAQ）的类似物。这些类似物是选择性、可逆的μ阿片受体（MOR）拮抗剂，具有良好的血脑屏障穿透性。这些化合物用于治疗阿片类药物成瘾和其他疾病和症状，包括用于疼痛治疗。
• 10.1016/j.bioorg.2024.107489
  作者：Flammia, Rachael、Huang, Boshi、Pagare, Piyusha P.、M. St. Onge, Celsey、Abebayehu, Abeje、Gillespie, James C.、Mendez, Rolando E.、Selley, Dana E.、Dewey, William L.、Zhang, Yan

  DOI：10.1016/j.bioorg.2024.107489

  日期：——

  activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine . Compound showed retention of the basic pharmacological attributes of while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound to examine whether it would serve as a new lead for opioid use disorder

  在过去 30 年中，与阿片类药物相关的过量死亡人数和患有阿片类药物使用障碍的个体人数显着增加。FDA 批准的治疗阿片类药物使用障碍的维持疗法可以成功抑制药物渴望并防止复发，但会产生降低患者依从性的不良反应。这就产生了对具有改善患者体验的新化学实体的需求。此前我们小组报道了一种新的先导化合物，一种 μ-阿片受体拮抗剂，可有效拮抗吗啡的抗伤害感受，并显示出显着的血脑屏障通透性。然而，属于含有噻吩的化合物，这些化合物是潜在氧化代谢的已知结构警报。为了克服这个问题，设计了 15 种在噻吩环 5' 位置具有不同取代基的衍生物，并研究了它们的构效关系。这些衍生物的结合亲和力、选择性和功能活性对其在 μ 阿片受体处的结合亲和力、选择性和功能活性进行了表征，并评估了它们拮抗吗啡的伤害性作用的能力。化合物显示出保留基本药理学属性，同时改善了阿片类药物依赖小鼠所经历的戒断效应。将进行进一步的研究以充分表征化合
• Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
  作者：Yunyun Yuan、Saheem A. Zaidi、David L. Stevens、Krista L. Scoggins、Philip D. Mosier、Glen E. Kellogg、William L. Dewey、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmc.2015.02.055

  日期：2015.4

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.
• Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
  作者：Yunyun Yuan、Orgil Elbegdorj、Irina O. Beletskaya、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmcl.2013.07.043

  日期：2013.9

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.
• 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.