Kinetic Interactions Between Carbamates (Quaternaries and Bisquaternaries of Dimethylcarbamoyloxypyridines), Human Acetylcholinesterase, and Oximes

In 2019, a subgroup of carbamate agents was added to the Schedules to the Chemical Weapons Convention, which are characterized by two positively charged amino groups with either one carbamate moiety for quaternaries or two carbamate moieties for bisquaternaries of dimethylcarbamoyloxypyridines. Limited data can be found in the open literature regarding these carbamates. We conducted an in vitro study to investigate the inhibition kinetics of human AChE as well as the effect of oximes on carbamylation and decarbamylation. The results confirmed these carbamates as potent inhibitors of human AChE showing second‐order inhibition rate constants ( k i ) ranging from 2.59 ± 0.19 × 10 8 (mol/L) −1 min −1 to 13.37 ± 0.24 × 10 8 (mol/L) −1 min −1 . The carbamates experienced a spectrum of effects in the presence of oximes resulting either in an increase or reduction of the k i values. For example, HLö‐7 had a significant effect on the inhibition kinetics of 1a (2.9‐fold). In addition, some oximes had a statistically relevant effect on the decarbamylation kinetics. Obidoxime or HLö‐7 significantly altered the decarbamylation kinetics of 1c , leading to increases by either a factor of 1.9 or 3.0. Furthermore, there was a decrease in decarbamylation for 1b in the presence of 2‐PAM and HI‐6. Despite these changes, the variation in decarbamylation kinetics might not significantly impact the overall effectiveness of carbamate prophylaxis. In conclusion, the interactions of AChE, the newly scheduled carbamates and oximes depend on small structural changes. The administration of HLö‐7 to humans poisoned by the carbamates cannot be recommended and the effect of pralidoxime, obidoxime, and HI‐6 on the carbamylation and decarbamylation have to be assessed for the individual combination of the carbamate and the oxime.