Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic

Huang Huoming; Wang Wenli; Xu Xuejun; Zhu Chen; Wang Yujun; Liu Jinggen; Li Wei; Fu Wei

首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic

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Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic

机译：发现3 - （（二甲基氨基）甲基）-4-羟基-4-（3-甲氧基苯基1）-N-苯基哌啶-1-甲酰胺作为新型有效镇痛

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Management of moderate to severe pain by clinically used opioid analgesics is associated with a plethora of side effects. Despite many efforts have been dedicated to reduce undesirable side effects, moderate progress has been made. In this work, starting from Tramadol, a series of 3-((dimethylamino)methyl)-4hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxamide derivatives were designed and synthesized, and their in vitro and in vivo activities were evaluated. Our campaign afforded selective opioid receptor (MOR) ligand 2a (K-i (MOR): 7.3 +/- 0.5 nM; K-iDOR: 849.4 +/- 96.6 nM; K-i KOR: 49.1 +/- 6.9 nM) as potent analgesic with ED50 of 3.1 mg/kg in 55 degrees C hot plate model. Its antinociception effect was blocked by opioid antagonist naloxone. High binding affinity toward MOR of compound 2a was associated with water bridge, salt bridge, hydrogen bond and hydrophobic interaction with MOR. The high selectivity of compound 2a for MOR over delta opioid receptor (DOR) and kappa opioid receptor (KOR) was due to steric hindrance of compound 2a with DOR and KOR. 2a, a compound with novel scaffold, could serve as a lead for the development of novel opioid ligands. (C) 2020 Elsevier Masson SAS. All rights reserved.

机译：通过临床使用的阿片类药物镇痛药进行中度至严重疼痛的管理与过多的副作用有关。尽管有许多努力致力于减少不期望的副作用，但已经取得了适度的进展。在这项工作中，从曲马多开始，设计并合成了一系列3 - （（二甲基氨基）甲基）-4羟基-4-（3-甲氧基苯基）哌啶-1-甲酰胺衍生物，并评估其体外和体内活性。我们的竞选提供了选择性阿片受体（Mor）配体2a（ki（mor）：7.3 +/- 0.5 nm; k-idor：849.4 +/- 96.6 nm; ki Kor：49.1 +/- 6.9 nm）作为ED50的有效镇痛55℃热板模型中为3.1毫克/千克。其抗湿润效应被阿片类药物拮抗剂纳洛酮阻断。对化合物2A的高结合亲和力与水桥，盐桥，氢键和与MOR的疏水相互作用有关。 MOR通过DELTA阿片受体（DOR）和Kappa阿片受体（KAPA OPIOID受体（KAPA）的高选择性是由于具有DOR和KOR的化合物2a的空间阻碍。如图2A所示，一种具有新型支架的化合物，可以用作新型阿片类配体的开发的铅。（c）2020 Elsevier Masson SAS。版权所有。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2020年第2020期|共14页
作者
Huang Huoming; Wang Wenli; Xu Xuejun; Zhu Chen; Wang Yujun; Liu Jinggen; Li Wei; Fu Wei;
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作者单位

Fudan Univ Sch Pharm Dept Med Chem Shanghai 201203 Peoples R China;

Fudan Univ Sch Pharm Dept Med Chem Shanghai 201203 Peoples R China;

Chinese Acad Sci Shanghai Inst Mat Med Shanghai 201203 Peoples R China;

Fudan Univ Sch Pharm Dept Med Chem Shanghai 201203 Peoples R China;

Chinese Acad Sci Shanghai Inst Mat Med Shanghai 201203 Peoples R China;

Chinese Acad Sci Shanghai Inst Mat Med Shanghai 201203 Peoples R China;

Fudan Univ Sch Pharm Dept Med Chem Shanghai 201203 Peoples R China;

Fudan Univ Sch Pharm Dept Med Chem Shanghai 201203 Peoples R China;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
Selective MOR agonists; Antinociception; Analgesic; Opioids; Molecular mechanism;

机译：选择性的Mor激动剂;抗休养液;镇痛剂;阿片类药物;分子机制;

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1. Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic [J] . Huang Huoming, Wang Wenli, Xu Xuejun, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2020,第期

机译：发现3 - （（二甲基氨基）甲基）-4-羟基-4-（3-甲氧基苯基1）-N-苯基哌啶-1-甲酰胺作为新型有效镇痛
2. The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one) [J] . Pike Kurt G., Barlaam Bernard, Cadogan Elaine, Journal of Medicinal Chemistry . 2018,第9期

机译：鉴定Ataxia Telanciectasia突变（ATM）激酶的有效，选择性和口服抑制剂：AZD0156的发现（8- {6- [3-（二甲基氨基）丙氧基] Pyridin-3-Y1} -3-甲基-1 - （四氢-2H-吡喃-4-基）-1,3-二氢-2H-咪唑[4,5-C]喹啉-2-一）
3. Discovery of 3-[2-(imidazo[1,2- b ]pyridazin-3-yl)ethynyl]-4-methyl- N -{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant [J] . Huang W.-S., Metcalf C.A., Sundaramoorthi R., Journal of Medicinal Chemistry . 2010,第12期

机译：3- [2-（咪唑并[1,2-b]哒嗪-3-基）乙炔基] -4-甲基-N- {4-[（4-甲基哌嗪-1-基）甲基] -3-（三氟甲基）苯基}苯甲酰胺（AP24534），一种具有T315I Gatekeeper突变体的断点簇区域abelson（BCR-ABL）激酶的有效，口服活性泛抑制剂
4. Effects of Methyl and Halogens in Analgesic Peptide Molecules for Their Potent Agonist Activities at MOR/DOR and Antagonist Activity at NK1R [C] . Aswini Kumar Giri, C.R. Apostol, P. Davis American Peptide Symposium . 2015

机译：镇痛肽分子在镇痛肽分子中甲基和卤素的影响Mor / Dor和NK1R拮抗剂活性的活性激动剂活性
5. Studies of the RAFT polymerization of acrylamide and N-[3-(dimethylamino)propyl] methacrylamide: Factors affecting kinetics, molecular weight control, and block copolymer formation. [D] . Thomas, David Bryan. 2003

机译：丙烯酰胺和N- [3-（二甲基氨基）丙基]甲基丙烯酰胺的RAFT聚合研究：影响动力学，分子量控制和嵌段共聚物形成的因素。
6. Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant [O] . Gabriela Alves de Souza, Soraia John da Silva, Catarina de Nigris Del Cistia, 2019

机译：发现新型的双活性3-（4-（二甲基氨基）苯基）-7-氨基烷氧基香豆素作为有效的选择性乙酰胆碱酯酶抑制剂和抗氧化剂
7. DESIGN AND SYNTHESIS OF NOVEL 1-((DIMETHYLAMINO)METHYL)-3-(4-(3-(SUBSTITUTE DPHENYL)-4-OXOTHIAZOLIDIN-2-YL)PHENYLIMINO)-5-NITROINDOLIN-2-ONES AS POTENT ANTITUBERCULAR AGENTS [O] . 2019

机译：新型1 - （（二甲基氨基）甲基）-3-（4-（用3-（替代Dphenyl）-4-甲醛唑烷-2-基）苯基咪唑酯作为有效的抗细胞剂的苯基咪唑酯的设计和合成
8. Summary of Health Effects Alleged by a Property Owner Following Potential Inhalation Exposure to a Chemical Mixture Manufactured or Processed by the Company with 2-Propanol, 1-(bis(3-(dimethylamino) propyl)amino); 1,3-Propanediamine, N1-(3-(dimethylamino)propyl)-N1, N3, N3-trimethyl; 1H-Imidazole, 1,2-dimethyl; 1,2-Dichloroethylene; 1,1,1,3,3-Pentafluoropropane; 2-Butoxyethanol. [R] . 2013

机译：在公司制造或加工的化学混合物中，使用2-丙醇，1-（双（3-（二甲基氨基）丙基）氨基）吸收潜在吸入后财产所有者所指称的健康影响摘要; 1,3-丙二胺，N1-（3-（二甲基氨基）丙基）-N1，N3，N3-三甲基; 1H-咪唑，1,2-二甲基; 1,2-二氯乙烯; 1,1,1,3,3-五氟丙烷; 2-丁氧基乙醇。

Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic

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