Inhibition of neurotoxic esterase in vitro by novel carbamates.

Abstract Carbamyl sulfonate (CS) compounds are a novel class of carbamates derived from amino acid methyl esters. They have the general structure RCH(COOCH 3 )NH(CO)SO 3 − K + , where R is the side-chain of the parent amino acid. These compounds were developed as active site-directed inhibitors of human leukocyte elastase (HLE). The purpose of this study was to characterize the inhibition of hen brain neurotoxic esterase (neuropathy target esterase, NTE), horse serum butyrylcholinesterase (BuChE), and bovine erythrocyte acetylcholinesterase (AChE) by CS analogs derived from the methyl esters of l -ala, d -norval, l -norval, l -phe, l -val, l -norleu, d -met, and l -met. Bimolecular rate constants of inhibition ( k i ) for NTE ranged from 0.571 for l -ala-CS to 17.7 m m −1 min −1 for l -norleu-CS (10-min I 50 values of 123 and 3.92 μ m , respectively). Potency against NTE increased with chain length for straight-chain R-groups of l -CS compounds. Unlike HLE, NTE was only weakly stereoselective for CS compound enantiomers. The l -isomers were weaker inhibitors of BuChE than NTE (10-min I 50 range of 742 to 35.6 μ m ). In contrast to the l -enantiomers, the I 50 plots of d -met-CS and d -norval-CS were not linear for BuChE, suggesting a possible stereospecific mechanistic shift for inhibition of this enzyme. AChE was not effectively inhibited by any of the CS compounds ( I 50 values > 750 μ m ). The specificity and charged nature of CS compounds give these unusual NTE inhibitors potential advantages for mechanistic studies of organophosphorus compound-induced delayed neurotoxicity (OPIDN) and its protection or potentiation.