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Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

GW280430A is an ultrashort-acting neuromuscular blocking agent and is targeted for muscle relaxation as part of the intubation surgical procedure. The objective of this work was to perform solid state characterization on GW280430A and to evaluate the relationship between water content and glass transition temperature (Tg). GW280430A was characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction (PXRD), microscopy and moisture sorption. The effect of water content on the Tg of GW280430A was evaluated by equilibrating the material over saturated salt solutions at a range of relative humidities (6.4-72.6%) and determining the Tg by DSC using hermetically sealed aluminum pans. GW280430A undergoes dehydration at 40 degrees C, glass transition at 130 degrees C and decomposition at 190 degrees C by differential scanning calorimetry. By PXRD and moisture sorption, GW280430A is an amorphous material and deliquesces at about 70% RH at room temperature. Water acts as a potent plasticizer for GW280430A and the Tg decreases significantly as the water content increases. No measurable decomposition of GW280430A was observed after 4 weeks at 40 degrees C/75% RH.

GW280430A is an ultrashort-acting neuromuscular blocking agent targeted at muscle relaxation to facilitate surgical intubation. The objective of this work was to study the buffer and cosolvent effects on the solution stability of GW280430A. The buffer catalytic effect was examined in citrate, malate, tartrate, and glycine by measuring the rate of degradation of GW280430A (0.2 mg/mL) at constant pH (3), ionic strength (0.15 M), and various buffer concentrations (0.01-0.05 M). The temperature dependence of the buffer catalytic effect and the degradation of the GW280430A in cosolvent (ethanol, propylene glycol, polyethylene glycol 400, N,N-dimethylacetamide)/water mixtures were studied at 40, 50, and 60 degrees C. The loss of parent drug was monitored by reverse-phase high-performance liquid chromatography. The degradation of GW280430A followed first-order kinetics in all buffer solutions. Significant buffer-catalyzed hydrolysis of GW280430A was observed with citrate, tartrate, and malate buffers, but not in glycine-buffered solutions. The activation energies in all buffered drug solutions ranged from 70 to 80 kJ/mol and decreased with increasing buffer concentration. GW280430A degradation was primarily through ester hydrolysis and followed first-order kinetics in aqueous solutions. In cosolvent/water mixtures, new degradation products were observed, indicating a chemical reaction between GW280430A and cosolvents. The reaction activation energies in the cosolvent/water mixtures ranged from 75 to 85 kJ/mol, with the longest t(0.9) at 5 degrees C equal to approximately 12 months and at 25 degrees C equal to 36 days. Consideration should be given to the incorporation of glycine or a low concentration of citrate, malate, or tartrate buffer in the parenteral formulation development of GW280430A. Cosolvents prolonged the predicted t(0.9) for GW280430A in solution, but the enhancement was not significant enough to pursue a liquidformulation.

Nonsymmetrical bisquaternary mono- and diesters combining the potency-enhancing properties of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have been studied as a means of promoting short action with high-potency neuromuscular block. Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short acting but showed varying degrees of vagal block.