Acyclic Cucurbit[n]uril-Type Containers as Receptors for Neuromuscular Blocking Agents: Structure-Binding Affinity...

Area of Science:

• Supramolecular Chemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Acyclic cucurbit[n]uril (CB[n]) molecular containers demonstrate strong binding to neuromuscular blocking agents (NMBAs) like rocuronium, vecuronium, pancuronium, and cisatracurium.
• Previous studies showed in vitro binding and in vivo reversal of neuromuscular block in rats by CB[n] compounds.

Purpose of the Study:

• To investigate the in vitro binding of various acyclic CB[n]-type receptors to NMBAs and acetylcholine.
• To establish structure-binding affinity relationships for these CB[n] receptors.
• To identify CB[n] variants with improved properties for potential in vivo applications.

Main Methods:

• Synthesis and characterization of diverse acyclic CB[n] receptor variants with modified aromatic sidewalls, glycoluril oligomer lengths, and linker lengths.
• Analysis of 1H NMR chemical shift changes upon complexation to elucidate binding modes.
• Determination of thermodynamic binding parameters using isothermal titration calorimetry (ITC).

Main Results:

• Binding interactions involve hydrophobic guest regions within the CB[n] cavity and cationic moieties interacting with ureidyl portals via ion-dipole and ion-ion forces.
• CB[n] receptors based on glycoluril trimers (hosts 4 and 5) exhibited weaker binding to steroidal NMBAs compared to those based on glycoluril tetramers (hosts 1 and 2C3).
• Modified aromatic sidewalls (hosts 1Me4 and 3) showed binding affinities similar to host 1, while hosts 2C2 and 2C4 displayed slightly weaker binding to NMBAs than 2C3 but retained acetylcholine discrimination and improved water solubility.

Conclusions:

• Structure-binding affinity relationships for acyclic CB[n] receptors and NMBAs were successfully developed.
• Host 2C4 demonstrates significant potential for future in vivo applications due to its binding properties, acetylcholine discrimination, and enhanced water solubility.