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Article(id=1241768178662052465, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241768176522957402, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.05.02, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1672675200000, receivedDateStr=2023-01-03, revisedDate=null, revisedDateStr=null, acceptedDate=1699459200000, acceptedDateStr=2023-11-09, onlineDate=1773990204729, onlineDateStr=2026-03-20, pubDate=1716566400000, pubDateStr=2024-05-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773990204729, onlineIssueDateStr=2026-03-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773990204729, creator=13701087609, updateTime=1773990204729, updator=13701087609, issue=Issue{id=1241768176522957402, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='5', pageStart='321', pageEnd='400', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773990204220, creator=13701087609, updateTime=1773992176593, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241776449330414547, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241768176522957402, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241776449330414548, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241768176522957402, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=327, endPage=333, ext={EN=ArticleExt(id=1241768180759204505, articleId=1241768178662052465, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Research progress in novel opioid drugs with reduced respiratory depression, columnId=1207314219599499390, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Opioid drugs activate G protein and （or） β-arrestin protein signaling pathways by acting on opioid receptors, which can generate analgesia and anesthesia effects, but the accompanying respiratory depression is a serious and common clinical problem. Until now, one of the goals of the basic research and therapeutic application of opioid drugs is to separate the analgesic effect from the respiratory depression side effect, so as to develop new opioid drugs with strong analgesic activity and reduced respiratory depression side effect. At present, peripheral selective opioid agonists, biased opioid agonists, mixed opioid agonists, endogenous opioid peptides and opioid splicing variant agonists have been developed successively, of which the biased opioid agonist oliceridine （TRV130） has been marketed. As the research progresses, more new opioid drugs will be used in clinical treatment to improve drug safety.

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阿片类药物通过激动阿片受体，激活G 蛋白、β -抑制蛋白等下游信号通路而发挥镇痛与麻醉效应，但引起的呼吸抑制是临床常见的严重问题。一直以来，阿片类药物基础和临床研究的目标之一是将镇痛作用与呼吸抑制作用分离，研发镇痛活性强、呼吸抑制作用减弱的新型阿片类药物。目前，外周选择性阿片受体激动剂、偏向性阿片受体激动剂、混合性阿片受体激动剂、内源性阿片肽和阿片受体剪接异构体激动剂等药物相继被研发，其中偏向性阿片激动剂奥赛利定（TRV130）已上市。随着研究的深入，将有更多新型阿片类药物用于临床治疗，以提高用药安全性。

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赵亮，E-mail:
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樊永正，男，主管药师，硕士，主要从事神经精神药理学研究，E-mail:

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樊永正，男，主管药师，硕士，主要从事神经精神药理学研究，E-mail:

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樊永正，男，主管药师，硕士，主要从事神经精神药理学研究，E-mail:

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opioids：阿片类药物，opioid receptor：阿片受体，cell membrane：细胞膜，β-arrestin：β-抑制蛋白，GTP：鸟嘌呤三核苷酸磷酸， adenylate cyclase：腺苷酸环化酶，cAMP：环磷酸腺苷，GRK：G蛋白偶联受体激酶，PKA：蛋白激酶A，endosome：核内体，lysosome：溶酶体，inhibit：抑制，decrease:减少，degrade:降解，recycle:循环，desensitization:脱敏，promote:促进

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呼吸抑制作用减弱的新型阿片类药物研究进展
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樊永正 , 韩丽君 , 赵亮
中国新药与临床杂志 | 综述 2024,43(5): 327-333
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中国新药与临床杂志 | 综述 2024, 43(5): 327-333
呼吸抑制作用减弱的新型阿片类药物研究进展
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樊永正 , 韩丽君, 赵亮
作者信息
  • 联勤保障部队第九九一医院 药剂科，湖北　襄阳　441000

    • 樊永正，男，主管药师，硕士，主要从事神经精神药理学研究，E-mail:

通讯作者:

赵亮，E-mail:
Research progress in novel opioid drugs with reduced respiratory depression
Yong-zheng FAN , Li-jun HAN, Liang ZHAO
Affiliations
  • Department of Pharmacy, the 991st Hospital of Joint Logistic Support Force, Xiangyang HUBEI 441000, China
出版时间: 2024-05-25 doi: 10.14109/j.cnki.xyylc.2024.05.02
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摘要
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阿片类药物通过激动阿片受体，激活G 蛋白、β -抑制蛋白等下游信号通路而发挥镇痛与麻醉效应，但引起的呼吸抑制是临床常见的严重问题。一直以来，阿片类药物基础和临床研究的目标之一是将镇痛作用与呼吸抑制作用分离，研发镇痛活性强、呼吸抑制作用减弱的新型阿片类药物。目前，外周选择性阿片受体激动剂、偏向性阿片受体激动剂、混合性阿片受体激动剂、内源性阿片肽和阿片受体剪接异构体激动剂等药物相继被研发，其中偏向性阿片激动剂奥赛利定（TRV130）已上市。随着研究的深入，将有更多新型阿片类药物用于临床治疗，以提高用药安全性。

镇痛药，阿片类  /  呼吸抑制  /  受体，阿片样  /  偏向性激动剂

Opioid drugs activate G protein and （or） β-arrestin protein signaling pathways by acting on opioid receptors, which can generate analgesia and anesthesia effects, but the accompanying respiratory depression is a serious and common clinical problem. Until now, one of the goals of the basic research and therapeutic application of opioid drugs is to separate the analgesic effect from the respiratory depression side effect, so as to develop new opioid drugs with strong analgesic activity and reduced respiratory depression side effect. At present, peripheral selective opioid agonists, biased opioid agonists, mixed opioid agonists, endogenous opioid peptides and opioid splicing variant agonists have been developed successively, of which the biased opioid agonist oliceridine （TRV130） has been marketed. As the research progresses, more new opioid drugs will be used in clinical treatment to improve drug safety.

analgesia, opioids  /  respiratory depression  /  receptors, opioids  /  biased agonists
樊永正, 韩丽君, 赵亮. 呼吸抑制作用减弱的新型阿片类药物研究进展. 中国新药与临床杂志, 2024 , 43 (5) : 327 -333 . DOI: 10.14109/j.cnki.xyylc.2024.05.02
Yong-zheng FAN, Li-jun HAN, Liang ZHAO. Research progress in novel opioid drugs with reduced respiratory depression[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (5) : 327 -333 . DOI: 10.14109/j.cnki.xyylc.2024.05.02
正文
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阿片类药物已经使用了上千年，广泛应用于术后中重度疼痛、麻醉诱导和术中维持，其至今仍无可替代，但阿片类药物在使用过程中常伴随呼吸抑制、尿潴留、成瘾、镇痛耐受、呕吐恶心和便秘等不良反应，其中围术期呼吸抑制发生率可达 0.5%~2%，严重的会危及生命［1］。目前，非阿片类镇痛药（如非甾体抗炎药）不能提供足够的镇痛效果或只对特定的疼痛情况有效（如钙离子通道阻滞剂加巴喷丁治疗成人疱疹感染的神经痛），而且也受其自身副作用的限制（如非甾体抗炎药引起的胃肠道出血），无法满足临床的实际需求。因此从阿片的受体结构、胞内作用机制等药理学方面研制呼吸抑制作用弱、镇痛作用强的新型阿片类药物，是降低死亡率的有效策略之一。
阿片类药物的作用机制
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阿片受体属于G蛋白耦联受体（GPCR），该类受体具有一个胞外氨基端区域（N端）和七个跨膜域及一个胞内羧基端尾区（C端）的基本结构。经典阿片受体主要包括µ受体（mu opioid receptor，MOR）、κ受体（kappa opoid receptor，KOR） 、δ受体（delta opioid receptor，DOR）和孤儿肽受体［nociceptin/orphanin FQ （N/OFQ） peptide receptor，NOR］，主要分布于中枢神经系统中脑、脑干的下行传导通路及脊髓背角，输精管、消化道、心脏及免疫系统等外周位点也广泛存在，参与调控疼痛、呼吸、应激、消化和体温等生理活动。外源性阿片物质或内源性阿片肽通过激活突触膜上阿片受体，使G蛋白的α亚基（Gα）与βγ亚基复合物（Gβγ）相互解离，Gα可以抑制腺苷酸环化酶（adenylate cyclase）的活性，减少细胞内环磷酸腺苷（cAMP）的生成，cAMP门控离子通道保持关闭，阻碍Na+内流；同时，Gβγ不仅抑制L型电压门控钙通道，防止Ca2+内流和神经元去极化，还激活G蛋白偶联的内向整流钾通道，促进K+外排和超极化，减弱神经元的兴奋性，抑制神经递质释放发挥镇痛等作用［2,3］。也有研究表明，阿片受体也可以通过β-抑制蛋白（β-arrestin）这条非 G 蛋白信号通路参与阿片受体脱敏、内化和回收等，如G蛋白偶联受体激酶（GRK）将阿片受体磷酸化后，β-arrestin可将受体移动到网格蛋白包被凹区，通过内吞作用，核内体将受体循环转运至胞内膜或溶酶体后使受体降解［4］。见图1。
阿片类药物致呼吸抑制的可能机制
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呼吸运动由复杂的脑干神经网络控制，主要受高级脑中枢、脑干中的中央化学感受器和颈动脉体外周化学感受器调控，同时各种兴奋性和抑制性神经递质及受体也参与调控呼吸节律［5］。研究表明，大脑脑干、臂旁核、延髓和脑桥均参与呼吸模式及节律的形成，如脑桥背外侧通过接收迷走神经元传入信号而调控呼吸频率，延髓背侧通过接收外周信号并投至脊髓神经元和延髓调节呼吸运动，其中位于脑干腹侧的前包钦格复合体一般被认为是维持呼吸节律的关键位点［6］，如向大鼠脑桥Kölliker-Fuse核团注射 MOR选择性激动剂DAMGO可引起大鼠潮气量、呼吸频率降低等［7］。位于外周颈动脉体上的Ⅰ型球细胞对血氧、CO2和pH值变化异常敏感，多数球细胞表现出脑啡肽免疫反应，脑啡肽可以减少颈动脉体活动，纳洛酮作用则相反。外源性阿片类物质激活位于上述位点的阿片受体后，可以使神经递质释放减少，从而抑制呼吸节律的产生和传导［8，9］，可表现为呼吸抑制、镇静和上气道张力减弱，最终可引起呼吸频率下降，潮气量减少，甚至呼吸暂停及死亡。
新型阿片类药物
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目前临床上大多数使用的镇痛药以阿片受体为靶点。阿片受体被激活后，胞内下游的不同信号通路可以激活不同的级联反应，由此引发不同的生物学效应。为了将阿片受体介导的麻醉镇痛与呼吸抑制作用分离，国内外学者研究了外周选择性阿片受体激动剂、偏向性阿片受体激动剂、混合性阿片受体激动剂、内源性阿片肽和阿片受体剪接异构体激动剂等，以期研发呼吸抑制弱、安全性高的新型阿片类药物。
1　外周选择性阿片受体激动剂
阿片镇痛主要由外周感觉神经元上阿片受体的激活介导，呼吸抑制等不良反应是由于中枢阿片受体激活而产生，仅激动外周阿片受体的药物引起呼吸抑制可能较弱［10-12］。有研究者对现有阿片受体激动剂进行改造，将一个氟原子结合到芬太尼母核乙烯桥上，使芬太尼氟化（酸化），得到了芬太尼类似物NFEPP，其解离常数为6.7，与炎症组织的pH值（5~7）接近，但与正常组织pH值（7.4）相差较远，从而外周选择性更强。在放射性配基结合实验中，NFEPP与放射性标记的内源性配体［3H］ DAMGO在结合位点存在竞争，表明NFEPP可能与MOR结合；在持续性或急性炎症性大鼠疼痛模型中，低剂量NFEPP仅在发炎（“受伤”）的爪子上产生剂量依赖性镇痛，而芬太尼在发炎和对侧（“未受伤”）的爪子上均产生镇痛，同时芬太尼可导致呼吸抑制而NFEPP致呼吸抑制却不明显［13］。此外，MOR拮抗剂naloxonemethiodide不能通过血脑屏障，但可以拮抗NFEPP的镇痛作用，且可部分逆转芬太尼的镇痛作用［13-15］，提示NFEPP可能仅作用于受损外周组织的MOR产生镇痛同时较少致呼吸抑制。JIMENEZ-VARGAS等［16］近期的一项研究成果也进一步证实了在结肠炎小鼠模型中，NFEPP优先激活位于发炎、偏酸化组织中的MOR，诱导抗炎反应而不会引起呼吸抑制。这为研制新型更安全的阿片类药物提供了良好的研究思路。
2　混合性阿片受体激动剂
混合性阿片受体激动剂可以减弱G蛋白信号和受体磷酸化，能有效减轻呼吸抑制等不良反应［17,18］。纳布啡和地佐辛是MOR/KOR部分激动剂，两者引起的呼吸抑制作用较弱，已在临床上广泛应用［19,20］。由 Ardent 公司研发的DPI-3290和 DPI-125属于二芳基甲基哌嗪化合物, 对DOR、MOR、KOR的激动作用强度分别为（4.29±0.36）、（11.10±3.04）和（16.57±4.14） nmoL·L-1，是阿片受体的混合性激动剂；在大鼠甩尾痛觉模型中, DPI-125表现出镇痛作用强、呼吸安全性高且滥用倾向低 ［21］。MP1104是一种DOR/KOR激动剂，在紫杉醇诱导的小鼠神经痛模型中，MP1104减轻了机械性痛和冷性痛，与吗啡不同的是，在小鼠全身体积描记法中没有观察到呼吸抑制［22］。有研究报道了一种NOR/MOR激动剂AT-121，它对NOR/MOR有部分激动活性，可以在成年恒河猴中发挥吗啡样镇痛作用，其镇痛作用比丁丙诺啡强，是吗啡的100倍，却对恒河猴的呼吸速率和通气量等没有影响，也未引起阿片类药物常见的不良反应［23,24］。BPR1M97是一种NOR/MOR完全激动剂，在一项C57小鼠甩尾痛觉实验［25］中，与吗啡组相比，BPR1M97组镇痛起效更快、给药后20 min内镇痛作用更强（P<0.001），且BPR1M97组血氧饱和度、呼吸频率、潮气量均显著高于吗啡组（P<0.001），说明BPR1M97是一种镇痛作用强、呼吸抑制作用弱的新型阿片类化合物。cebranopadol也是一种NOR/MOR完全激动剂，一项Ⅰ期临床试验给予健康志愿者（n=12）cebranopadol 600 mg单次口服，受试者最小通气量均大于0 L·min-1，同等剂量下全MOR激动剂则会引起呼吸暂停，提示cebranopadol呼吸抑制作用可能较弱［26］。以上研究表明，混合性阿片受体激动剂具有良好的镇痛效力和较弱的呼吸抑制作用，值得进一步深入研究。
3　偏向性阿片受体激动剂
随着对G 蛋白信号通路研究的不断深入，有研究证实配体在激活G 蛋白介导的经典信号通路同时，另外一条由β-arrestin介导的平行信号通路也可能被激活，且不同的配体对这两条通路的激活程度不同，甚至只偏向性激活其中之一，最终表现在整体动物水平上的药理效应有所不同，如镇痛、欣快感和躯体依赖主要由G 蛋白信号通路介导，而呼吸抑制则是由β-arrestin 信号通路介导［27,28］。这提示如果配体偏向性激活 G 蛋白信号通路，那么可能在产生镇痛的同时，呼吸抑制作用将会大大减弱，偏向性信号通路的发现以及偏向性配体理论的提出给设计新型阿片类药物提供了思路。基于该理论，新型阿片受体激动剂TRV-130［29］、PZM21［30］和SR1701861［31］先后被研发，研究者们认为有效的G蛋白偏向性激动剂、低β-arrestin招募及信号介导，可能具有高镇痛、弱呼吸抑制的效果。TRV130是Trevena公司基于MOR晶体结构研发的，与吗啡相比，cAMP累积法检测显示 TRV130约有84%偏向G蛋白信号通路，Path Hunter 酶互补法检测显示TRV130仅约15%偏向β-arrestin 通路，提示其具有明显的G蛋白信号通路偏向性［32］。临床试验结果表明，TRV130的镇痛效果与吗啡相当，但起效更快，呼吸抑制发生率更低、程度更弱，提示在临床上使用TRV130可能有良好的获益-风险比［33-36］。PZM21是MANGLIK等［30］通过分子对接技术，虚拟筛选到的MOR的G蛋白偏向性激动剂，与吗啡相比，其激活G蛋白通路活性相当、无β-arrestin招募活性。但HILL等［37］研究发现，PZM21会以一种类似吗啡方式致小鼠呼吸抑制。进一步的研究表明，由于对G蛋白偏向性检测方法的不同，PZM21有可能属于内在疗效偏低的化合物，而不是G蛋白偏向的化合物［38,39］。因此，MOR偏向性激动剂依然是一个新兴及热议的研究领域。
4　内源性阿片肽
阿片受体被发现后，研究人员继而发现大脑中有类似阿片类物质的活动，且与阿片受体有亲和力，统称为内啡肽。内啡肽对MOR有高度选择性，相对传统外源性阿片类药物，内啡肽类似物可有效减少受体下调、耐受和脱敏等的发生率，因此呼吸抑制作用较弱［40］。但内啡肽体内不稳定，易被酶水解代谢，因此研究者通过开发脑啡肽酶抑制剂［41］、改造具有潜在药理特性的内啡肽类似物［42］来增加内源性阿片肽浓度。内啡肽-1类似物ZH853在正常小鼠的热板痛觉模型中发挥的镇痛效果与吗啡相当，全身体积描记法实验表明ZH853 5.6 mg·kg-1静脉注射对正常SD大鼠分钟通气量的抑制作用显著小于吗啡10 mg·kg-1（P<0.000 1）［43］，提示ZH853镇痛作用强、呼吸抑制作用弱。CYX-6是一种内啡肽-2类似物，大鼠脑室给药可产生与吗啡相近的镇痛活性，而引起便秘和呼吸抑制的作用极小［44］。此外，阿片受体的变构调节剂可以影响正构配体与受体的亲和力和效价［45］，正性变构调节剂可增强内源性阿片肽的激动活性，增强内源性配体激动阿片受体活性，从而减轻呼吸抑制。如正性变构调节剂BMS-986122可以通过稳定阿片受体的活性状态，增加内源性阿片肽Met-enkephalin对G蛋白激活水平，在保留对小鼠的镇痛作用同时呼吸抑制作用明显减弱［46,47］。但由于上述化合物合成的复杂性限制了成药研究，且安全性及有效性也有待进一步考察，因此目前尚未见相关临床研究报道。
5　阿片受体剪接异构体激动剂
MOR的基因在体内存在广泛选择性剪接行为，选择性剪接发生在脱氧核糖核酸转化为信使核糖核酸的过程中，其中外显子的结合方式不同，可生成多种受体亚型［48］。依据跨膜结构的不同分为仅含外显子1的截短型1TM（1 transmembrane）剪接异构体、含外显子11不含外显子1的截短型6TM剪接异构体和含外显子11及外显子1的7TM全长结构域剪接异构体，其中体内存在的大多数受体是7TM［49］。1TM不与阿片类药物直接结合，主要通过伴侣蛋白间接增强7TM的表达及药理作用［50］。研究发现，以6TM为靶标的几种阿片类药物具有镇痛作用强、呼吸抑制作用弱的特点［51］。在野生型小鼠和缺乏7TM剪接异构体的小鼠脑膜匀浆中，可以检测到放射性标记的碘苯甲羟氨甲酰胺（3-iodobenzoyl-6β-naltrexamide, IBNtxA）结合位点，但在外显子11敲除小鼠中未检测到，提示IBNtxA可能是6TM 剪接异构体中的一种新型MOR激动剂［52,53］。在正常C57小鼠热板痛觉实验中，IBNtxA 3 mg·kg-1静脉注射可以达到与吗啡10 mg·kg-1相近的镇痛活性［54］，提示IBNtxA是一种非常有效的镇痛药。MAJUMDAR等［55］进一步研究证实IBNtxA 2.5 mg·kg-1皮下注射对正常小鼠呼吸频率的抑制作用要明显低于吗啡20 mg·kg-1（P<0.001），且与生理盐水对小鼠呼吸频率的影响无显著差异，提示IBNtxA可能具有镇痛性强、呼吸抑制作用弱的优点，然而IBNtxA胞内具体信号通路作用机制及临床效果有待进一步探究。
6　其他
丁丙诺啡和TRV130都有相似的G蛋白偏向性激活作用，但与TRV130相比，丁丙诺啡从MOR中解离的速度明显较慢，这种差异可能会导致临床效果显著不同，如丁丙诺啡致呼吸抑制作用较轻［56］。阿片受体不同亚型之间或和其他G蛋白偶联受体可以形成二聚体或寡聚体，两个受体在物理上相互联系，激活后可以表现出与单一受体不同的药理学特性，在体外细胞培养模型中MOR-DOR异二聚体被证实存在共表达［57］。有研究证实6’-guanidinonaltrindole可以激动DOR-KOR异二聚体，在外周感觉神经元中表现出独特的信号和功能调控作用，从而发挥镇痛作用而不产生呼吸抑制等不良反应［58,59］。此外，有研究发现激动阿片受体的不同亚型后会产生不同程度呼吸抑制及镇痛效果，如给予大鼠MOR选择性激动剂DAMGO或DOR选择性激动剂DPDPE均会产生明显呼吸抑制，而给予选择性KOR激动剂U-50488H 则呼吸抑制不明显［60］。然而，目前还没有相应的化合物进入临床研究。
结语
收起
由于阿片类药物致呼吸抑制是致命的不良反应，在过去几十年里，许多疼痛研究学者都试图研发可取代阿片类药物的新药，但大多收效甚微。因此改良阿片类药物，研发呼吸抑制作用弱、安全性高的新型阿片类药物是众多学者研究的一个热点。目前比较有前景的是偏向性阿片受体激动剂的研发，其中奥赛利定（TRV-130，商品名：Olinvyk）已于2023年4月28日正式获得国家药品监督管理局批准上市，用于治疗成人患者中需要静脉注射阿片类药物的急性疼痛，也可作为替代疗法效果不佳时的选择。随着对阿片受体结构、胞内信号通路等作用机制的不断揭示及相关研究的深入，其他新型候选药物及其类似物将来也可能用于治疗临床上的各种类型疼痛，甚至可能部分取代现有的常用阿片类药物，从而降低手术过程中呼吸抑制的发生率，提高麻醉镇痛用药的安全性。
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doi: 10.14109/j.cnki.xyylc.2024.05.02
  • 接收时间：2023-01-03
  • 首发时间：2026-03-20
  • 出版时间：2024-05-25
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  • 收稿日期：2023-01-03
  • 录用日期：2023-11-09
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    联勤保障部队第九九一医院 药剂科，湖北　襄阳　441000

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多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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