Article(id=1196886671179432454, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1196886663541600644, articleNumber=1001-2494(2024)22-2107-09, orderNo=null, doi=10.11669/cpj.2024.22.002, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1720368000000, receivedDateStr=2024-07-08, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1763289619487, onlineDateStr=2025-11-16, pubDate=1732204800000, pubDateStr=2024-11-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763289619487, onlineIssueDateStr=2025-11-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763289619487, creator=13701087609, updateTime=1763289619487, updator=13701087609, issue=Issue{id=1196886663541600644, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='22', pageStart='2099', pageEnd='2196', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763289617666, creator=13701087609, updateTime=1763292152892, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1196897297100488858, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1196886663541600644, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1196897297104683163, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1196886663541600644, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2107, endPage=2115, ext={EN=ArticleExt(id=1196886671447867912, articleId=1196886671179432454, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Recent Advances in Dual/Multi-Targeted Analgesics Based on μ Opioid Receptor, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Pain management remains as a global public health issue, with 20% of the adult population worldwide impacted and many patients still suffer from unrelieved or undertreated pain. Classic opioids exert antinociceptive effects by activating μ opioid receptor (MOR), but they are associated with many side effects (including respiratory depression, addiction, and constipation) which have aggravated the ongoing and escalating opioid crisis in worldwide. Therefore, there is an urgent need for the development of novel analgesics free of MOR-mediated unwanted adverse effects. Multi-target therapeutics target two or more related targets in a disease network system simultaneously, which can potentially provide greater efficacy and improve treatment outcomes compared with single-target therapies. Due to the key role of MOR in regulating pain signal transmission, MOR-based multi-target ligands have been accepted as one of the mainstream strategies for designing new potent analgesics without side effects. In this review, recent advances in multitarget-directed drugs toward MOR are summarized, which may provide references for the development of potent and safer analgesics.

, correspAuthors=Tao ZHUANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Xiaomin HAN, Mingyue YIN, Jie SONG, Tao ZHUANG), CN=ArticleExt(id=1196886956874449711, articleId=1196886671179432454, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=基于μ阿片受体的双/多靶点镇痛药物研究进展, columnId=1190352408384471863, journalTitle=中国药学杂志, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

疼痛的治疗与管理是与人类生活息息相关的全球公共卫生安全问题,各种疼痛困扰着全世界约20%的成年人。传统的阿片类镇痛药物主要通过激活μ阿片受体(μ opioid receptor, MOR)而发挥镇痛效果,但其普遍存在呼吸抑制、成瘾、便秘等严重副作用,在全球范围内造成日益严重的“阿片危机”现象。因此针对无/低副作用镇痛药物的研发显得尤为重要与迫切。多靶点药物治疗策略针对疾病网络系统中的两个或多个相关靶点,可以同步调节复杂疾病网络系统中的多个环节,从而实现更优的临床疗效与安全性。在疼痛药物研究领域,鉴于MOR在疼痛信号通路中的重要作用,基于MOR的双/多靶点药物研发也已成为无/低副作用镇痛药物研究的主流策略之一。本文对近年来报道的MOR双/多靶点药物进行综述,以期为基于MOR的无/低副作用镇痛药物的研发提供参考。

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韩晓敏,女,硕士研究生 研究方向:新型镇痛药物研究

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Neurosci Bull, 2023, 39: 1655-1668., articleTitle=Blockade of the dopamine D₃ receptor attenuates opioids-induced addictive behaviours associated with inhibiting the mesolimbic dopamine system, refAbstract=null), Reference(id=1197125033509302461, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, doi=null, pmid=null, pmcid=null, year=2021, volume=64, issue=null, pageStart=7778, pageEnd=7808, url=null, language=null, rfNumber=[76], rfOrder=75, authorNames=BONIFAZI A, BATTITI F O, SANCHEZ J, journalName=J Med Chem, refType=null, unstructuredReference=BONIFAZI A, BATTITI F O, SANCHEZ J, et al. Novel dual-target μ-opioid receptor and dopamine D₃ receptor ligands as potential nonaddictive pharmacotherapeutics for pain management[J]. J Med Chem, 2021, 64: 7778-7808., articleTitle=Novel dual-target μ-opioid receptor and dopamine D₃ receptor ligands as potential nonaddictive pharmacotherapeutics for pain management, refAbstract=null), Reference(id=1197125033576411326, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, doi=null, pmid=null, pmcid=null, year=2023, volume=66, issue=null, pageStart=10304, pageEnd=10341, url=null, language=null, rfNumber=[77], rfOrder=76, authorNames=BONIFAZI A, SAAB E, SANCHEZ J, journalName=J Med Chem, refType=null, unstructuredReference=BONIFAZI A, SAAB E, SANCHEZ J, et al. Pharmacological and physicochemical properties optimization for dual-target dopamine D₃ (D₃R) and μ-opioid (MOR) receptor ligands as potentially safer analgesics[J]. J Med Chem, 2023, 66: 10304-10341., articleTitle=Pharmacological and physicochemical properties optimization for dual-target dopamine D₃ (D₃R) and μ-opioid (MOR) receptor ligands as potentially safer analgesics, refAbstract=null), Reference(id=1197125033660297407, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, doi=null, pmid=null, pmcid=null, year=2023, volume=131, issue=null, pageStart=106335, pageEnd=null, url=null, language=null, rfNumber=[78], rfOrder=77, authorNames=GAO M, ZHANG Y, WANG B, journalName=Bioorg Chem, refType=null, unstructuredReference=GAO M, ZHANG Y, WANG B, et al. Novel dual-target μ-opioid and TRPV1 ligands as potential pharmacotherapeutics for pain management[J]. Bioorg Chem, 2023, 131: 106335., articleTitle=Novel dual-target μ-opioid and TRPV1 ligands as potential pharmacotherapeutics for pain management, refAbstract=null), Reference(id=1197125033781932224, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, doi=null, pmid=null, pmcid=null, year=2022, volume=23, issue=null, pageStart=674, pageEnd=null, url=null, language=null, rfNumber=[79], rfOrder=78, authorNames=WITKOWSKA E, GODLEWSKA M, OSIEJUK J, journalName=Int J Mol Sci, refType=null, unstructuredReference=WITKOWSKA E, GODLEWSKA M, OSIEJUK J, et al. Bifunctional opioid/melanocortin peptidomimetics for use in neuropathic pain: variation in the type and length of the linker connecting the two pharmacophores[J]. 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J Pharmacol Exp Ther, 2022, 383: 182-198., articleTitle=Interactive effects of μ-opioid and adrenergic-α ₂ receptor agonists in rats: pharmacological investigation of the primary kratom alkaloid mitragynine and its metabolite 7-hydroxymitragynine, refAbstract=null), Reference(id=1197125033949704386, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, doi=null, pmid=null, pmcid=null, year=2024, volume=67, issue=null, pageStart=9355, pageEnd=9373, url=null, language=null, rfNumber=[81], rfOrder=80, authorNames=LI P, ZHANG Q, ZHENG H, journalName=J Med Chem, refType=null, unstructuredReference=LI P, ZHANG Q, ZHENG H, et al. Discovery of ITI-333, a novel orally bioavailable molecule targeting multiple receptors for the treatment of pain and other disorders[J]. J Med Chem, 2024, 67: 9355-9373., articleTitle=Discovery of ITI-333, a novel orally bioavailable molecule targeting multiple receptors for the treatment of pain and other disorders, refAbstract=null)], funds=[Fund(id=1197125025653370990, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, awardId=82304275, language=CN, fundingSource=国家自然科学基金项目(82304275), fundOrder=null, country=null), Fund(id=1197125025724674159, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, awardId=23KJB350002, language=CN, fundingSource=江苏省高等学校自然科学研究项目(23KJB350002), fundOrder=null, country=null), Fund(id=1197125025779200112, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, awardId=KYCX2024-19, language=CN, fundingSource=江苏省研究生科研与实践创新计划项目(KYCX2024-19), fundOrder=null, country=null), Fund(id=1197125025842114673, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, awardId=KYCX2023-44, language=CN, fundingSource=江苏省研究生科研与实践创新计划项目(KYCX2023-44), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1197125021287100474, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, xref=null, ext=[AuthorCompanyExt(id=1197125021295489083, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, companyId=1197125021287100474, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmacy, Jiangsu Ocean University, Lianyungang 222000, China), AuthorCompanyExt(id=1197125021303877692, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, companyId=1197125021287100474, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=江苏海洋大学药学院, 江苏 连云港 222000)])], figs=[ArticleFig(id=1197125024038563930, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=ySx4T3LT627HIlHOoVLeVQ==, figureFileBig=zvV0P8XHln8/kH8yaoesiA==, tableContent=null), ArticleFig(id=1197125024126644315, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图1, caption=μ阿片受体(MOR)介导的疼痛信号通路^[11], figureFileSmall=ySx4T3LT627HIlHOoVLeVQ==, figureFileBig=zvV0P8XHln8/kH8yaoesiA==, tableContent=null), ArticleFig(id=1197125024214724700, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=H38QxQlLCVyW/bQfHGqbeg==, figureFileBig=RCz1+gqbJzmwNSdCAcjnAA==, tableContent=null), ArticleFig(id=1197125024298610781, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图2, caption=基于MOR的多靶点药物开发的合理性^[14], figureFileSmall=H38QxQlLCVyW/bQfHGqbeg==, figureFileBig=RCz1+gqbJzmwNSdCAcjnAA==, tableContent=null), ArticleFig(id=1197125024361525342, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=/ZBcYEKjGUpS7I+3OL4gyQ==, figureFileBig=3AqoqOqDZccnmjNE0UiTaQ==, tableContent=null), ArticleFig(id=1197125024437022815, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图3, caption=μ阿片受体/去甲肾上腺素转运体(MOR/NET)多靶点活性配体^[17,21-22]

K_iμ-化合物对μ阿片受体的结合亲和力;K_iNET-化合物对去甲肾上腺素转运体的结合亲和力; K_iSERT-化合物对5-羟色胺转运体的结合亲和力。

, figureFileSmall=/ZBcYEKjGUpS7I+3OL4gyQ==, figureFileBig=3AqoqOqDZccnmjNE0UiTaQ==, tableContent=null), ArticleFig(id=1197125024499937376, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=v4epQ6HkoMRfs2mAidOXWA==, figureFileBig=aSlcX+bL67wo61P+DTUb0g==, tableContent=null), ArticleFig(id=1197125024588017761, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图4, caption=μ阿片受体/孤啡肽受体(MOR/NOP)双靶点活性配体^[26,29-34]

K_iNOP-化合物对孤啡肽受体的结合亲和力;K_iδ-化合物对δ阿片受体的结合亲和力;K_iκ-化合物对κ阿片受体的结合亲和力。

, figureFileSmall=v4epQ6HkoMRfs2mAidOXWA==, figureFileBig=aSlcX+bL67wo61P+DTUb0g==, tableContent=null), ArticleFig(id=1197125024680292450, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=aszxYcJSvBDwB/ZrbcqDGA==, figureFileBig=6OkOnzfIzvb4sI2/8WET6A==, tableContent=null), ArticleFig(id=1197125024747401315, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图5, caption=μ阿片受体/δ阿片受体(MOR/DOR)双靶点活性配体^[41-43], figureFileSmall=aszxYcJSvBDwB/ZrbcqDGA==, figureFileBig=6OkOnzfIzvb4sI2/8WET6A==, tableContent=null), ArticleFig(id=1197125024831287396, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=rg1Vtds+k+yvD/lzeMCJyQ==, figureFileBig=hLL9oTM81f2zYT59Ur3vOA==, tableContent=null), ArticleFig(id=1197125024910979173, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图6, caption=μ阿片受体/κ阿片受体(MOR/KOR)双靶点活性配体^[45,47]

K_iκ-化合物对κ阿片受体的结合亲和力。

, figureFileSmall=rg1Vtds+k+yvD/lzeMCJyQ==, figureFileBig=hLL9oTM81f2zYT59Ur3vOA==, tableContent=null), ArticleFig(id=1197125024990670950, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=QONUrtEtPLxnwmJrdNYjCQ==, figureFileBig=WtWFp4++xRDyLWeYh35aHw==, tableContent=null), ArticleFig(id=1197125025057779815, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图7, caption=μ阿片受体/Sigma-1受体(MOR/σ₁R)双靶点活性配体^[53-57]

EC₅₀μ-化合物与μ阿片受体结合时产生50%最大生物效应的浓度;K_iσ₁-化合物对Sigma-1受体的结合亲和力。

, figureFileSmall=QONUrtEtPLxnwmJrdNYjCQ==, figureFileBig=WtWFp4++xRDyLWeYh35aHw==, tableContent=null), ArticleFig(id=1197125025133277288, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=tTYYTFOt8CfpgBvgBrxWYA==, figureFileBig=tgc9PPumGiLpQ+SimMdwUA==, tableContent=null), ArticleFig(id=1197125025212969065, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图8, caption=μ阿片受体/大麻素受体(MOR/CBR)双靶点活性配体^[65-66]

K_iCBR-化合物对大麻素受体的结合亲和力。

, figureFileSmall=tTYYTFOt8CfpgBvgBrxWYA==, figureFileBig=tgc9PPumGiLpQ+SimMdwUA==, tableContent=null), ArticleFig(id=1197125025317826666, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=LTw64kE6g9tFUTiULlT/dg==, figureFileBig=8oxKtP5hK9+ygJKMl+46Rw==, tableContent=null), ArticleFig(id=1197125025384935531, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图9, caption=μ阿片受体/神经肽FF受体(MOR/NPFFR)双靶点活性配体^[67-72]

K_iNPFF1R-化合物对神经肽FF1受体的结合亲和力;K_iNPFF2R-化合物对神经肽FF2受体的结合亲和力;EC₅₀NPFF1R-化合物与神经肽FF1受体结合时产生50%最大生物效应的浓度;EC₅₀NPFF2R-化合物与神经肽FF2受体结合时产生50%最大生物效应的浓度。

, figureFileSmall=LTw64kE6g9tFUTiULlT/dg==, figureFileBig=8oxKtP5hK9+ygJKMl+46Rw==, tableContent=null), ArticleFig(id=1197125025435267180, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=EN, label=null, caption=null, figureFileSmall=mpuLc9Gpr1g8iA8rlazPlQ==, figureFileBig=SLryw2z5OAFDCCQwP/DZOw==, tableContent=null), ArticleFig(id=1197125025498181741, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886671179432454, language=CN, label=图10, caption=μ阿片受体/多巴胺D₃受体(MOR/D₃R)双靶点活性配体

K_iD₃R-化合物对多巴胺D3受体的结合亲和力。

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