Fluorinated Ultralong-Acting Neuromuscular Blocking Agent with Improved Activity Profile and Biosafety for the Development of Blockade and Reversal Partner Drugs.

Halogenation has been used as a useful strategy to optimize an imidazolium-based macrocyclic ultralong-acting neuromuscular blocking agent for improved bioactivity and biocompatibility. A structure-activity relationship study for 18 compounds reveals that monofluorinated macrocycle IMC-X5 displays blockade profiles generally superior to those of lead compound IMC-0. In vivo tests with a rat model show that, compared with those of IMC-0, the onset, profound blockade, and moderate blockade-to-spontaneous respiration times of IMC-X5 at the same dose of 0.2 mg/kg shortens by 47%, extends by 34%, and shortens by 89%, respectively, while the onset activity surpasses that of cisatracurium, one of the main neuromuscular blocking agents, of a clinically associated dose. Moreover, the profound blockade of IMC-X5 can be rapidly reversed by a biocompatible acyclic cucurbit[n]uril (ACB) antagonist at any stage of blockade. IMC-X5 also exhibits a biosafety superior to that of IMC-0. The two agents thus form a promising partnership featuring ultralong-acting blockade and on-demand reversal.