Discovery of an Ultralong-acting Nondepolarizing Neuromuscular Blocker That Displays Short Onset Time and On-Demand Rapid Reversal by a Biocompatible Antagonist

Abstract

The combination of ultralong-acting neuromuscular block and subsequent on-demand rapid reversal may provide prolonged surgeries with improved conditions by omitting continuous or repetitive blocker administration, enabling a more stable and predictable hemodynamic profile and eliminating residual block. For this target, we prepared 19 imidazolium-incorporated tetracationic macrocycles. In vivo studies with rats revealed that one macrocycle (IMC-14) displays extremely high blocking activity. At the dose of 12.5-fold ED₉₀, IMC-14 exhibits an onset time shorter than that of cisatracurium of 2-fold dose and a duration time corresponding to more than 13 h for human adults. Moreover, within the dose range of 12.5–187.5-fold ED₉₀, the profound block induced by IMC-14 can be rapidly reversed at any stage by a highly biocompatible acyclic cucurbit[n]uril antagonist, with a reversal time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, a clinically widely used intermediate-acting neuromuscular blocking agent.