Hana S. Alhamadsheh, Roshanak Rahimian, Miki Park, Mamoun M. Alhamadsheh, Hala Aldawod
{"title":"用于阿片类药物安全输送的长效吗啡前药的设计。","authors":"Hana S. Alhamadsheh, Roshanak Rahimian, Miki Park, Mamoun M. Alhamadsheh, Hala Aldawod","doi":"10.1002/cmdc.202500499","DOIUrl":null,"url":null,"abstract":"<p>Effective opioid management in neonatal abstinence syndrome (NAS) and opioid use disorder (OUD) requires maintaining low, stable plasma opioid levels to prevent withdrawal without central side effects. Current treatments rely on frequent opioid dosing, such as oral morphine every few hours for up to 3 weeks in NAS, leading to plasma level fluctuations and increased risk of toxicity or withdrawal. Herein, the design and characterization of AG10-L-E2-morphine, a prodrug that forms a zwitterionic subcutaneous depot for sustained morphine release is reported. In rats, a single subcutaneous dose of AG10-L-E2-morphine maintained plasma morphine levels for over 72 h without inducing respiratory depression, even at high doses. The prodrug is stable in human plasma and specifically activated by liver carboxylesterase enzyme 2 (CES2), supporting its safety and translational potential. This long-acting system could improve NAS care by enabling convenient dosing and early integration of nonpharmacologic strategies, ultimately reducing hospital stays and healthcare burden.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 17","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design of a Long-Acting Morphine Prodrug for Safe Opioid Delivery\",\"authors\":\"Hana S. Alhamadsheh, Roshanak Rahimian, Miki Park, Mamoun M. Alhamadsheh, Hala Aldawod\",\"doi\":\"10.1002/cmdc.202500499\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Effective opioid management in neonatal abstinence syndrome (NAS) and opioid use disorder (OUD) requires maintaining low, stable plasma opioid levels to prevent withdrawal without central side effects. Current treatments rely on frequent opioid dosing, such as oral morphine every few hours for up to 3 weeks in NAS, leading to plasma level fluctuations and increased risk of toxicity or withdrawal. Herein, the design and characterization of AG10-L-E2-morphine, a prodrug that forms a zwitterionic subcutaneous depot for sustained morphine release is reported. In rats, a single subcutaneous dose of AG10-L-E2-morphine maintained plasma morphine levels for over 72 h without inducing respiratory depression, even at high doses. The prodrug is stable in human plasma and specifically activated by liver carboxylesterase enzyme 2 (CES2), supporting its safety and translational potential. This long-acting system could improve NAS care by enabling convenient dosing and early integration of nonpharmacologic strategies, ultimately reducing hospital stays and healthcare burden.</p>\",\"PeriodicalId\":147,\"journal\":{\"name\":\"ChemMedChem\",\"volume\":\"20 17\",\"pages\":\"\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemMedChem\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202500499\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202500499","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
新生儿戒断综合征(NAS)和阿片类药物使用障碍(OUD)的有效阿片类药物管理需要维持低、稳定的血浆阿片类药物水平,以防止无中枢副作用的戒断。目前的治疗依赖于频繁给药阿片类药物,如在NAS中每隔几小时口服吗啡长达3周,导致血浆水平波动,增加毒性或停药的风险。本文报道了ag10 - l - e2 -吗啡的设计和表征,ag10 - l - e2 -吗啡是一种形成两性离子皮下储库以持续释放吗啡的前药。在大鼠中,单次皮下剂量的ag10 - l - e2 -吗啡维持血浆吗啡水平超过72小时,即使在高剂量下也不会引起呼吸抑制。前药在人血浆中稳定,可被肝羧酸酯酶2 (CES2)特异性激活,支持其安全性和转化潜力。这种长效系统可以通过方便给药和早期整合非药物策略来改善NAS治疗,最终减少住院时间和医疗负担。
Design of a Long-Acting Morphine Prodrug for Safe Opioid Delivery
Effective opioid management in neonatal abstinence syndrome (NAS) and opioid use disorder (OUD) requires maintaining low, stable plasma opioid levels to prevent withdrawal without central side effects. Current treatments rely on frequent opioid dosing, such as oral morphine every few hours for up to 3 weeks in NAS, leading to plasma level fluctuations and increased risk of toxicity or withdrawal. Herein, the design and characterization of AG10-L-E2-morphine, a prodrug that forms a zwitterionic subcutaneous depot for sustained morphine release is reported. In rats, a single subcutaneous dose of AG10-L-E2-morphine maintained plasma morphine levels for over 72 h without inducing respiratory depression, even at high doses. The prodrug is stable in human plasma and specifically activated by liver carboxylesterase enzyme 2 (CES2), supporting its safety and translational potential. This long-acting system could improve NAS care by enabling convenient dosing and early integration of nonpharmacologic strategies, ultimately reducing hospital stays and healthcare burden.
期刊介绍:
Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs.
Contents
ChemMedChem publishes an attractive mixture of:
Full Papers and Communications
Reviews and Minireviews
Patent Reviews
Highlights and Concepts
Book and Multimedia Reviews.