Structure–Activity Relationship Studies Leading to the Discovery of Highly Water-Soluble and Biocompatible Acyclic Cucurbit[<i>n</i>]uril FY-3451 as a Universal Antagonist That Rapidly Reverses Neuromuscular Blocking Agents <i>In Vivo</i>
The development of a reversal agent that can rapidly reverse clinically used nondepolarizing neuromuscular blocking agents (NMBAs) has long been a challenge. Here, we report the synthesis of a series of highly water-soluble acyclic cucurbit[<i>n</i>]urils (acCBs). Systematic structure-activity relationship studies reveal that introducing two propylidene units on the peripheral benzene rings not only remarkably improves the activity of the corresponding derivative <b>acCB6</b> (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium, vecuronium, and pancuronium, the four clinically used NMBAs, through stable inclusion, but also allows for high water-solubility as well as a maximum tolerated dose (2000 mg/kg on rats). <i>In vivo</i> experiments with rats show that, at the identical dose of 25 mg/kg, for rocuronium, vecuronium, and pancuronium, <b>acCB6</b> can achieve a recovery time shorter than that of sugammadex for rocuronium and, at the dose of 100 mg/kg, realize comparably rapid reversal for cisatracurium.
Authors
- Furong Lin (ORCID: https://orcid.org/0000-0001-5732-6253)
- Zhuo Lei (ORCID: https://orcid.org/0000-0001-6042-6810)
- Wei Zhou (ORCID: https://orcid.org/0000-0001-7467-3628)
- Q. Li (ORCID: https://orcid.org/0000-0001-7025-0644)
- Zhan‐Ting Li (ORCID: https://orcid.org/0000-0003-3954-0015)
- Dan‐Wei Zhang (ORCID: https://orcid.org/0000-0003-1244-1850)
- Da Ma (ORCID: https://orcid.org/0000-0002-5300-7500)
- Qiao‐Yan Qi
- Jia Tian (ORCID: https://orcid.org/0000-0002-8339-0563)
- Shang‐Bo Yu (ORCID: https://orcid.org/0000-0001-7186-367X)
- Jingyu Yang (ORCID: https://orcid.org/0000-0002-4632-6597)
- Jiangshan Zhang (ORCID: https://orcid.org/0000-0002-2345-8511)
- Sheng‐Yi Zhuang (ORCID: https://orcid.org/0000-0001-5652-6202)
- Yan Wu (ORCID: https://orcid.org/0000-0001-5474-5663)
- Yue-Yang Liu
- Ke Feng (ORCID: https://orcid.org/0000-0003-2024-6393)
- Yang Zong (ORCID: https://orcid.org/0000-0002-9402-2715)
Institutions
- Fudan University (CN)
- Shanghai Institute of Organic Chemistry (CN)
- University of Chinese Academy of Sciences (CN)
- Taizhou University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01960
- Citations
- 13
- Primary Topic
- Supramolecular Chemistry and Complexes
- Type
- article
- Field-Weighted Citation Impact
- 3.25
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality