组胺H_3受体拮抗剂/反向激动剂的研究与设计
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- 英文论文题名：Research and Design of Novel Histamine H_3 Receptor Antagonists/Inverse Agonists
- 论文作者：兰昱 ; 李景 ; 张伶莉 ; 宋金春
- 英文论文作者：LAN Yu ; LI Jing ; ZHANG Ling-li ; SONG Jin-chun ; Department of Pharmacy ; Renmin Hospital of Wuhan University
- 年：2016
- 作者机构：武汉大学人民医院药学部;
- 论文关键词：组胺H_3受体 ; 拮抗剂 ; 3D-QSAR ; 药效团模型 ; 镇痛活性
- 英文论文关键词：histamine H_3 receptor ; antagonist/inverse agonist ; 3D-QSAR pharmacophore model ; anti-nociceptive effect
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：中文
- 分类号：R91
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：8
- 文件大小：805k
- 原文格式：O
- 会议级别：全国
摘要
目的:构建组胺H_3受体拮抗剂/反转激动剂的三维定量构效关系(3D-QSAR)药效团模型,并以此设计具有神经痛镇痛活性的配体分子。方法:应用Discovery Studio 2.5,基于已有文献进行建模,对模型进行评价和验证,然后应用模型进行虚拟筛选,并对筛选所得化合物进行神经痛活性评价。结果:建立了具有活性预测能力的3D-QSAR药效团模型,并通过该模型成功筛选到具有组胺H_3受体亲和生和镇痛活性的化合物。结论:所构建的3D-QSAR药效团模型具有较好的预测能力,能用于指导组胺H_3受体拮抗剂/反向激动剂的药物分子设计。所筛选的化合物具有镇痛活性,有待进行更深入的药理活性评价
Objective To construct the three-dimensional quantitative structure-activity relationship(3D-QSAR) pharmacophore model of histamine H_3 receptor antagonist/inverse agonist,and design anti-neuropathic pain ligand on the basis of the model.METHODSDiscovery studio 2.5 was used to generate the pharmacophore model with published literatures.The pharmacophore model was validated and assessed,and used for virtual screening.The compounds retrieved from virtual screening were evaluated in in vitro binding assay and test in mice formalin model.RESULTSOne satisfactory 3D-QSAR pharmacophore model with good predictive capabihty was built.Through virtual screening a compound with good receptor affinity and anti-nociceptive effect was obtained.CONCLUSIONThe 3D-QSAR pharmacophore model showed good predictive capabihty,which could be applied to design novel histamine H_3 receptor antagonists/inverse agonists.The compounds from virtual screening possesses potent anti-nociceptive effects,Further studies of this compound are currently underway.
Objective To construct the three-dimensional quantitative structure-activity relationship(3D-QSAR) pharmacophore model of histamine H_3 receptor antagonist/inverse agonist,and design anti-neuropathic pain ligand on the basis of the model.METHODSDiscovery studio 2.5 was used to generate the pharmacophore model with published literatures.The pharmacophore model was validated and assessed,and used for virtual screening.The compounds retrieved from virtual screening were evaluated in in vitro binding assay and test in mice formalin model.RESULTSOne satisfactory 3D-QSAR pharmacophore model with good predictive capabihty was built.Through virtual screening a compound with good receptor affinity and anti-nociceptive effect was obtained.CONCLUSIONThe 3D-QSAR pharmacophore model showed good predictive capabihty,which could be applied to design novel histamine H_3 receptor antagonists/inverse agonists.The compounds from virtual screening possesses potent anti-nociceptive effects,Further studies of this compound are currently underway.
引文
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[6]Panula P,Nuutinen S.The histaminergic network in the brain:basic organization and role in disease[J].Nat RevNeumsci,2013,14(7):472-487.
[7]Hsieh G C,Honore P,Pai M,et al.Antinociceptive effects of histamine H3 receptor antagonist in the preclinical models of pain in rats and the involvement of central noradrenergic systems[J].Brain Res,2010,1354:74-84.
[8]Cowart M,Hsieh G,Black L A,et al.Pharmacological characterization of A-960656,a histamine H(3)receptor antagonist with efficacy in animal models of osteoarthritis and neuropathic pain[J].Eur J Pharmacol,2012,684(1-3):87-94.
[9]Lepailleur A,Freret T,Lemaitre S,et al.Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties:pharmacophore-based virtual screening and polypharmacology[J].J Chemlnf Model,2014,54(6):1773-1784.
[10]LetavicMA,Keith JM,Ly KS,et al.2-Aryloxymethylmorpholine histamine H(3)antagonists[J].Bioorg Med ChemLett,2008,18(21):5796-5799.
[11]Nersesian DL,Black LA,Miller TR,et al.In vitro SAR of pyrrolidme-containing histamine H3 receptor antagonists:trends across multiple chemical series[J].Bioorg Med ChemLett,2008,18(1):355-359.
[12]Pierson P D,FettesA,FreichelC,et al.5-hydroxyindole-2-carboxylic acid amides:novel histamine-3 receptor inverse agonists for the treatment of obesity[J]J Med Chem,2009,52(13):3855-3868.
[13]Altenbach R J,Black LA,StrakhovaMI,et al.Diaryldiamines with dual inhibition of the histamine H(3)receptor and the norepinephrine transporter and the efficacy of 4-(3-(memylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-l-yl)ethoxy)naphthalene-1-ol in pain[J]J Med Chem,2010,53(21):7869-7873.
[14]Gao Z,Hurst W J,Hall D,et al.Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy[J].BioorgMed Chem,2015,23(3):429-438.
[15]Lan Y,Chen Y,Cao X D,et al.Synthesis and biological evaluation of novel sigma-1 receptor antagonists based on pyrimidine scaffold as agents for treating neuropathic pain[J].J Med Chem,2014,57(24):10404-10423.
[2]Gilron I,Dickenson AH.Emerging drugs for neuropathic pain[J].Expert OpinEmerg Drugs,2014,19(3):329-341.
[3]Knezevic N N,Cicmil N,Knezevic I,et al.Discontinued neuropathic pain therapy between 2009-2015[J]?xpert OpinlnvestigDrugs,2015,24(12):1631-1646.
[4]Arrang J M,Garbarg M,Schwartz J C.Auto-inhibition of brain histamine release mediated by a novel class(H3)of histamine receptor[J].Nature,1983,302(5911):832-837.
[5]Berlin M,Boyce C W,Ruiz Mde L.Histamine H3 receptor as a drug discovery target[J]J Med Chem,2011,54(1):26-53.
[6]Panula P,Nuutinen S.The histaminergic network in the brain:basic organization and role in disease[J].Nat RevNeumsci,2013,14(7):472-487.
[7]Hsieh G C,Honore P,Pai M,et al.Antinociceptive effects of histamine H3 receptor antagonist in the preclinical models of pain in rats and the involvement of central noradrenergic systems[J].Brain Res,2010,1354:74-84.
[8]Cowart M,Hsieh G,Black L A,et al.Pharmacological characterization of A-960656,a histamine H(3)receptor antagonist with efficacy in animal models of osteoarthritis and neuropathic pain[J].Eur J Pharmacol,2012,684(1-3):87-94.
[9]Lepailleur A,Freret T,Lemaitre S,et al.Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties:pharmacophore-based virtual screening and polypharmacology[J].J Chemlnf Model,2014,54(6):1773-1784.
[10]LetavicMA,Keith JM,Ly KS,et al.2-Aryloxymethylmorpholine histamine H(3)antagonists[J].Bioorg Med ChemLett,2008,18(21):5796-5799.
[11]Nersesian DL,Black LA,Miller TR,et al.In vitro SAR of pyrrolidme-containing histamine H3 receptor antagonists:trends across multiple chemical series[J].Bioorg Med ChemLett,2008,18(1):355-359.
[12]Pierson P D,FettesA,FreichelC,et al.5-hydroxyindole-2-carboxylic acid amides:novel histamine-3 receptor inverse agonists for the treatment of obesity[J]J Med Chem,2009,52(13):3855-3868.
[13]Altenbach R J,Black LA,StrakhovaMI,et al.Diaryldiamines with dual inhibition of the histamine H(3)receptor and the norepinephrine transporter and the efficacy of 4-(3-(memylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-l-yl)ethoxy)naphthalene-1-ol in pain[J]J Med Chem,2010,53(21):7869-7873.
[14]Gao Z,Hurst W J,Hall D,et al.Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy[J].BioorgMed Chem,2015,23(3):429-438.
[15]Lan Y,Chen Y,Cao X D,et al.Synthesis and biological evaluation of novel sigma-1 receptor antagonists based on pyrimidine scaffold as agents for treating neuropathic pain[J].J Med Chem,2014,57(24):10404-10423.
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