• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

5'-芳基-14-烷氧基吡啶并吗啡烷类的合成及构效关系研究：具有系统镇痛活性和减轻阿片类副作用的μ阿片受体激动剂/δ阿片受体拮抗剂配体的鉴定。

Synthesis and Structure-Activity Relationships of 5'-Aryl-14-alkoxypyridomorphinans: Identification of a μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Ligand with Systemic Antinociceptive Activity and Diminished Opioid Side Effects.

机构信息

Chemistry Department, Southern Research, Birmingham, Alabama 35205, United States.

Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.

出版信息

J Med Chem. 2020 Jul 23;63(14):7663-7694. doi: 10.1021/acs.jmedchem.0c00503. Epub 2020 Jun 30.

DOI:10.1021/acs.jmedchem.0c00503
PMID:32530286
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9521336/
Abstract

We previously identified a pyridomorphinan (, SRI-22138) possessing a 4-chlorophenyl substituent at the 5'-position on the pyridine and a 3-phenylpropoxy at the 14-position of the morphinan as a mixed μ opioid receptor (MOR) agonist and δ/κ opioid receptor (DOR/KOR) antagonist with potent antinociceptive activity and diminished tolerance and dependence in rodents. Structural variations at the 5'- and 14-positions of this molecule gave insights into the structure-activity relationships for binding and functional activity. Subtle structural changes exerted significant influence, particularly on the ability of the compounds to function as agonists at the MOR. In vivo evaluation identified compound (SRI-39067) as a MOR agonist/DOR antagonist that produced systemically active potent antinociceptive activity in tail-flick assay in mice, with diminished tolerance, dependence/withdrawal, reward liability, and respiratory depression versus morphine. These results support the hypothesis that mixed MOR agonist/DOR antagonist ligands may emerge as novel opioid analgesics with reduced side effects.

摘要

我们之前发现一种吡啶并吗啡烷（，SRI-22138），其在吡啶的 5'-位具有 4-氯苯基取代基，在吗啡烷的 14-位具有 3-苯丙氧基，作为混合 μ 阿片受体（MOR）激动剂和 δ/κ 阿片受体（DOR/KOR）拮抗剂，具有强大的镇痛活性，并且在啮齿动物中减少了耐受性和依赖性。该分子在 5'-位和 14-位的结构变化为结合和功能活性的构效关系提供了深入了解。细微的结构变化产生了显著的影响，特别是对化合物作为 MOR 激动剂的作用能力的影响。体内评估确定化合物（SRI-39067）是一种 MOR 激动剂/DOR 拮抗剂，在小鼠的尾部闪烁试验中产生全身有效的强效镇痛活性，与吗啡相比，减少了耐受性、依赖性/戒断、奖赏倾向和呼吸抑制。这些结果支持了这样一种假设，即混合 MOR 激动剂/DOR 拮抗剂配体可能成为新型阿片类镇痛药，副作用减少。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/ab12a19b54b2/nihms-1836420-f0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/49f079e60356/nihms-1836420-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/196c54c1db67/nihms-1836420-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/aa434df3d72a/nihms-1836420-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/5f9084f5292e/nihms-1836420-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/768f468c68c5/nihms-1836420-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/bdb69600ffa6/nihms-1836420-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/5c939c48952d/nihms-1836420-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/6af1c82d6c83/nihms-1836420-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/3573ee6dc309/nihms-1836420-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/5dcef2133f9b/nihms-1836420-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/a844b7a70d80/nihms-1836420-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/8deaa6731256/nihms-1836420-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/371a1496acd8/nihms-1836420-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/cf86c3f1d267/nihms-1836420-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/b610401e4920/nihms-1836420-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/37a24e53b164/nihms-1836420-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/ab12a19b54b2/nihms-1836420-f0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/49f079e60356/nihms-1836420-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/196c54c1db67/nihms-1836420-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/aa434df3d72a/nihms-1836420-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/5f9084f5292e/nihms-1836420-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/768f468c68c5/nihms-1836420-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/bdb69600ffa6/nihms-1836420-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/5c939c48952d/nihms-1836420-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/6af1c82d6c83/nihms-1836420-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/3573ee6dc309/nihms-1836420-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/5dcef2133f9b/nihms-1836420-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/a844b7a70d80/nihms-1836420-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/8deaa6731256/nihms-1836420-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/371a1496acd8/nihms-1836420-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/cf86c3f1d267/nihms-1836420-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/b610401e4920/nihms-1836420-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/37a24e53b164/nihms-1836420-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d762/9521336/ab12a19b54b2/nihms-1836420-f0017.jpg

相似文献

1
Synthesis and Structure-Activity Relationships of 5'-Aryl-14-alkoxypyridomorphinans: Identification of a μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Ligand with Systemic Antinociceptive Activity and Diminished Opioid Side Effects.5'-芳基-14-烷氧基吡啶并吗啡烷类的合成及构效关系研究：具有系统镇痛活性和减轻阿片类副作用的μ阿片受体激动剂/δ阿片受体拮抗剂配体的鉴定。
J Med Chem. 2020 Jul 23;63(14):7663-7694. doi: 10.1021/acs.jmedchem.0c00503. Epub 2020 Jun 30.
2
14-Alkoxy- and 14-acyloxypyridomorphinans: μ agonist/δ antagonist opioid analgesics with diminished tolerance and dependence side effects.14-烷氧基-和 14-酰氧基吡啶并吗啡烷类：具有降低的耐受性和依赖性副作用的 μ 激动剂/δ 拮抗剂阿片类镇痛药。
J Med Chem. 2012 Oct 11;55(19):8350-63. doi: 10.1021/jm300686p. Epub 2012 Sep 27.
3
Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities.UMB 425 的合成、建模和药理学评价，一种具有降低耐受性风险的混合 μ 激动剂/δ 拮抗剂阿片类镇痛药。
ACS Chem Neurosci. 2013 Sep 18;4(9):1256-66. doi: 10.1021/cn4000428. Epub 2013 Jun 11.
4
Novel ligands for the opioid receptors: synthesis and structure-activity relationships among 5'-aryl and 5'-heteroaryl 17-cyclopropylmethyl-4,5 alpha-epoxypyrido[2',3':6,7]morphinans.阿片受体的新型配体：5'-芳基和5'-杂芳基17-环丙基甲基-4,5α-环氧吡啶并[2',3':6,7]吗啡喃的合成及其构效关系
Bioorg Med Chem. 2003 Sep 1;11(18):4143-54. doi: 10.1016/s0968-0896(03)00432-2.
5
Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety.吲哚苯部分被取代的纳曲吲哚类似物的合成、阿片受体结合及生物活性测定。
J Med Chem. 1998 Jul 16;41(15):2872-81. doi: 10.1021/jm980083i.
6
Identification of opioid ligands possessing mixed micro agonist/delta antagonist activity among pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone [correction of hydropmorphone].在源自纳洛酮、羟吗啡酮和氢吗啡酮[纠正为氢吗啡酮]的吡啶吗啡喃类化合物中鉴定具有混合μ激动剂/δ拮抗剂活性的阿片样物质配体。
J Med Chem. 2004 Mar 11;47(6):1400-12. doi: 10.1021/jm030311v.
7
Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands.作为混合效能μ阿片受体/δ阿片受体配体，6位具有多种极性取代基的四氢喹啉类化合物的不对称合成及其体外和体内活性
ACS Chem Neurosci. 2015 Aug 19;6(8):1428-35. doi: 10.1021/acschemneuro.5b00100. Epub 2015 May 13.
8
Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.生物可利用的、具有混合效应的μ-阿片受体（MOR）激动剂/δ-阿片受体（DOR）拮抗剂的进一步优化与评估：平衡MOR和DOR亲和力
J Med Chem. 2015 Nov 25;58(22):8952-69. doi: 10.1021/acs.jmedchem.5b01270. Epub 2015 Nov 13.
9
Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.吡咯并和吡啶吗啡喃类：非选择性阿片受体拮抗剂以及δ阿片受体激动剂/μ阿片受体部分激动剂。
Bioorg Med Chem. 2014 Aug 1;22(15):4067-72. doi: 10.1016/j.bmc.2014.05.065. Epub 2014 Jun 12.
10
Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.芳胺取代物生成高效能、有效混合μ-阿片受体（MOR）/δ-阿片受体（DOR）肽类似物，具有增强的代谢稳定性。
J Med Chem. 2020 Feb 27;63(4):1671-1683. doi: 10.1021/acs.jmedchem.9b01818. Epub 2020 Feb 10.

引用本文的文献

1
Applications of Bridgehead Heterocycles in Drug Design and Medicinal Chemistry.桥头杂环在药物设计和药物化学中的应用。
Top Curr Chem (Cham). 2025 Mar 21;383(2):16. doi: 10.1007/s41061-025-00502-2.
2
Opioid system and related ligands: from the past to future perspectives.阿片类系统及相关配体：从过去到未来的展望
J Anesth Analg Crit Care. 2024 Oct 11;4(1):70. doi: 10.1186/s44158-024-00201-2.
3
Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment.抑制脊髓特异性 hsp90 同工型揭示了一种提高阿片类药物治疗治疗指数的新策略。

本文引用的文献

1
Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.芳胺取代物生成高效能、有效混合μ-阿片受体（MOR）/δ-阿片受体（DOR）肽类似物，具有增强的代谢稳定性。
J Med Chem. 2020 Feb 27;63(4):1671-1683. doi: 10.1021/acs.jmedchem.9b01818. Epub 2020 Feb 10.
2
Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine.脑室内给予 CYX-6，一种强效的 μ 阿片受体激动剂、δ 和 κ 阿片受体拮抗剂以及 μ、δ 和 κ 阿片受体的偏向配体，与吗啡相比，可诱发大鼠的镇痛作用，同时最小化便秘和呼吸抑制。
Eur J Pharmacol. 2020 Mar 15;871:172918. doi: 10.1016/j.ejphar.2020.172918. Epub 2020 Jan 17.
3
Sci Rep. 2024 Jun 26;14(1):14715. doi: 10.1038/s41598-024-65637-6.
4
Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.一种低风险抗伤害性双功能 MOR/DOR 环肽的鉴定和药理学特征。
Molecules. 2023 Nov 11;28(22):7548. doi: 10.3390/molecules28227548.
5
Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy.硝基苄叉氧吗啡酮，一种具有高μ阿片受体效能的双功能μ和δ阿片受体配体。
Front Pharmacol. 2023 Jul 3;14:1230053. doi: 10.3389/fphar.2023.1230053. eCollection 2023.
6
HSP90 inhibition in the mouse spinal cord enhances opioid signaling by suppressing an AMPK-mediated negative feedback loop.在小鼠脊髓中抑制 HSP90 可通过抑制 AMPK 介导的负反馈环来增强阿片类信号。
Sci Signal. 2023 Apr 11;16(780):eade2438. doi: 10.1126/scisignal.ade2438.
7
The Downregulation of Opioid Receptors and Neuropathic Pain.阿片受体下调与神经病理性疼痛。
Int J Mol Sci. 2023 Mar 22;24(6):5981. doi: 10.3390/ijms24065981.
8
Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists.新型 δ 阿片受体（DOR）反向激动剂和不可逆（非竞争性）拮抗剂的发现。
Molecules. 2021 Nov 5;26(21):6693. doi: 10.3390/molecules26216693.
9
Recent Chemical and Pharmacological Developments on 14-Oxygenated--methylmorphinan-6-ones.近期 14-氧代-甲基吗啡烷-6-酮的化学和药理学研究进展。
Molecules. 2021 Sep 18;26(18):5677. doi: 10.3390/molecules26185677.
10
SAR Matrices Enable Discovery of Mixed Efficacy μ-Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore.SAR 矩阵通过芳香胺药效团使具有简化结构的混合效力 μ-阿片受体激动剂肽模拟物的发现成为可能。
ACS Chem Neurosci. 2021 Jan 6;12(1):216-233. doi: 10.1021/acschemneuro.0c00693. Epub 2020 Dec 21.
Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.阐明具有肽和小分子激动剂的活性 δ-阿片受体晶体结构。
Sci Adv. 2019 Nov 27;5(11):eaax9115. doi: 10.1126/sciadv.aax9115. eCollection 2019 Nov.
4
Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids.综合分子药理学筛选揭示了临床相关阿片类药物的潜在新受体相互作用。
PLoS One. 2019 Jun 6;14(6):e0217371. doi: 10.1371/journal.pone.0217371. eCollection 2019.
5
Multivalent peptide and peptidomimetic ligands for the treatment of pain without toxicities and addiction.多价肽和拟肽配体治疗疼痛，无毒性和成瘾性。
Peptides. 2019 Jun;116:63-67. doi: 10.1016/j.peptides.2019.02.004. Epub 2019 Apr 20.
6
Bifunctional opioid receptor ligands as novel analgesics.双功能阿片受体配体作为新型镇痛药。
Neuropharmacology. 2019 Jun;151:195-207. doi: 10.1016/j.neuropharm.2019.03.006. Epub 2019 Mar 8.
7
Respiratory depression and brain hypoxia induced by opioid drugs: Morphine, oxycodone, heroin, and fentanyl.阿片类药物引起的呼吸抑制和脑缺氧：吗啡、羟考酮、海洛因和芬太尼。
Neuropharmacology. 2019 Jun;151:219-226. doi: 10.1016/j.neuropharm.2019.02.008. Epub 2019 Feb 5.
8
(-)-Hardwickiic Acid and Hautriwaic Acid Induce Antinociception via Blockade of Tetrodotoxin-Sensitive Voltage-Dependent Sodium Channels.(-)-硬毛猕猴桃酸和豪特瓦酸通过阻断河豚毒素敏感型电压门控钠离子通道诱导镇痛作用。
ACS Chem Neurosci. 2019 Mar 20;10(3):1716-1728. doi: 10.1021/acschemneuro.8b00617. Epub 2018 Dec 20.
9
Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels.桦木酸来源于沙漠薰衣草 Hyptis emoryi，通过阻断 N 型和 T 型钙通道来减轻紫杉醇、HIV 和神经损伤相关的周围感觉神经病变。
Pain. 2019 Jan;160(1):117-135. doi: 10.1097/j.pain.0000000000001385.
10
Synthesis and Evaluation of a Novel Bivalent Selective Antagonist for the Mu-Delta Opioid Receptor Heterodimer that Reduces Morphine Withdrawal in Mice.新型μ-δ阿片受体杂二聚体选择性拮抗剂的合成与评价，可减少小鼠的吗啡戒断反应。
J Med Chem. 2018 Jul 26;61(14):6075-6086. doi: 10.1021/acs.jmedchem.8b00403. Epub 2018 Jul 16.