Kinetics and Mechanisms of Acetylcholinesterase and Butyrylcholinesterase Inhibition by Cardiovascular Drugs and Benzodiazepines

The goal of this work is to determine enzyme kinetics and mechanisms of acetylcholinesterase and butyrylcholinesterase inhibition by five cardiovascular drugs, lovastatin, simvastatin, amlodipine besylate, nifedipine, and hydralazine hydrochloride, and two benzodiazepines, diazepam and chlordiazepoxide hydrochloride. All drugs in this study are reversible mixed‐type inhibitors of acetylcholinesterase and butyrylcholinesterase. The pK_i values for acetylcholinesterase and butyrylcholinesterase inhibition by the cardiovascular drugs are linearly correlated with the molecular weights of the drugs with the slopes of 0.005 and 0.0021, respectively. Therefore, van der Waals' interactions between acetylcholinesterase and the cardiovascular drugs are stronger than those between butyrylcholinesterase and the drugs. This is probably due to a smaller active site gorge and a more significant peripheral anionic substrate binding site of acetylcholinesterase than those of butyrylcholinesterase. The fact that the pK_i values for both butyrylcholinesterase and acetylcholinesterase inhibition by the cardiovascular drugs are linearly correlated with each other suggests that both enzyme inhibition reactions proceed via a common mechanism. Furthermore, amlodipine besylate may be useful in Alzheimer's disease treatment similar to donepezil.