Structure-activity relationship of reversible cholinesterase inhibitors including paraquat

Abstract

The inhibitory effect of paraquat on cholinesterase activity was investigated in comparison with four paraquat derivatives, six monoquaternary ammoniums and six anticholinergic drugs. Inhibitor concentrations to cause 50% inhibition (I⁵⁰) and Hill coefficients for three enzymes, human erythrocyte acetylcholinesterase (AChE), Electrophorus electricus AChE and human plasma butyrylcholinesterase (BuChE) were measured. The results obtained were as follows. The I⁵⁰ for erythrocyte AChE was similar to the I⁵⁰ for eel AChE. Secondary to edrophonium, diethylparaquat, paraquat, morfamquat and monoquat showed lower I⁵⁰ for AChE, and possessed higher inhibition selectivity (IS), expressed as the ratio of I⁵⁰ for BuChE to I⁵⁰ for erythrocyte AChE. However, diquat showed higher I⁵⁰ for AChE and lower IS, similar to the other monoquaternary ammoniums. A negative correlation was observed between log [I⁵⁰ for erythrocyte AChE] and log [IS], among paraquat and its derivatives, monoquaternary ammoniums and anticholinergic drugs, respectively. With respect to Hill coefficients, these inhibitors could be classified into four groups, [1] competitive inhibitors: diquat, edrophonium, choline, tetramethylammonium and trimethylphenylammonium, [2] inhibitors showing negative cooperativity: paraquat, diethylparaquat, morfamquat, d- tubocurarine, atropine, gallamine and nicotine, [3] moderate type inhibitors: monoquat, hexamethonium and decamethonium. [4] the other type inhibitors showing positive cooperativity for erythrocyte AChE: tetraethylammonium and ethyltrimethylammonium.