INHIBITION OF NEUROTOXIC ESTERASE IN-VITRO BY NOVEL CARBAMATES

Carbamyl sulfonate (CS) compounds are a novel class of carbamates deri ved from amino acid methyl esters. They have the general structure RCH (COOCH3)NH(CO)SO3-K+, where R is the sidechain of the parent amino aci d. These compounds were developed as active site-directed inhibitors o f human leukocyte elastase (HLE). The purpose of this study was to cha racterize the inhibition of hen brain neurotoxic esterase (neuropathy target esterase, NTE), horse serum butyrylcholinesterase (BuChE), and bovine erythrocyte acetylcholinesterase (AChE) by CS analogs derived f rom the methyl esters of L-ala, D-norval, L-norval, L-phe, L-val, L-no rleu, D-met, and L-met. Bimolecular rate constants of inhibition (ki) for NTE ranged from 0.571 for L-ala-CS to 17.7 mM(-1) min(-1) for L-no rleu-CS (10-min 150 values of 123 and 3.92 mu M, respectively). Potenc y 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 BuCh E than NTE (10-min 150 range of 742 to 35.6 mu M). In contrast to the L-enantiomers, the 150 plots of D-met-CS and D-norval-CS were not line ar for BuChE, suggesting a possible stereospecific mechanistic shift f or inhibition of this enzyme. AChE was not effectively inhibited by an y of the CS compounds (150 values > 750 mu M) The specificity and char ged nature of CS compounds give these unusual NTE inhibitors potential advantages for mechanistic studies of organophosphorus compound-induc ed delayed neurotoxicity (OPIDN) and its protection or potentiation. ( C) 1997 Academic Press.