Structure–Activity\nRelationship Studies Leading\nto the Discovery of Highly Water-Soluble and Biocompatible Acyclic\nCucurbit[<i>n</i>]uril FY-3451 as a Universal Antagonist\nThat Rapidly Reverses Neuromuscular Blocking Agents <i>I

The\ndevelopment of a reversal agent that can rapidly reverse clinically\nused nondepolarizing neuromuscular blocking agents (NMBAs) has long\nbeen a challenge. Here, we report the synthesis of a series of highly\nwater-soluble acyclic cucurbit[<i>n</i>]urils (acCBs). Systematic\nstructure–activity relationship studies reveal that introducing\ntwo propylidene units on the peripheral benzene rings not only remarkably\nimproves the activity of the corresponding derivative <b>acCB6</b> (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium,\nvecuronium, and pancuronium, the four clinically used NMBAs, through\nstable inclusion, but also allows for high water-solubility as well\nas 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,\nfor rocuronium, vecuronium, and pancuronium, <b>acCB6</b> can\nachieve a recovery time shorter than that of sugammadex for rocuronium\nand, at the dose of 100 mg/kg, realize comparably rapid reversal for\ncisatracurium.