engleski

Bronchodilating beta2-agonists as human cholinesterase inhibitors

Beta2-agonists are one of three types of prescription bronchodilating drugs. They possess the ability to relieve bronchoconstriction. Besides dilating bronchial passages, this class of compounds also causes vasodilation in muscles and liver, relaxation of the uterine muscle, and insulin release. Also, recent studies suggest that chronic treatment with certain bronchodilating beta2-agonists relieves neuropathic pain. The beneficial effect of bronchodilators albuterol and adrenaline in congenital myasthenic syndrome and congenital endplate acetylcholinesterase deficiency has already been proven. Terbutaline, isoproterenol and metaproterenol have been demonstrated to be reversible cholinesterase inhibitors. Most bronchodilators are derivatives of catecholamines, resorcinol or saligenin. We focused our research on resorcinol (fenoterol), catecholamine (isoetharine and adrenaline), and saligenine (albuterol) derivatives as inhibitors of human acetylcholinesterase (AChE ; EC. 3.1.1.7) and of the usual, atypical and fluoride-resistant butyrylcholinesterase (BChE ; EC 3.1.1.8). As a measure of inhibition potency, we determined the dissociation constants of the enzyme-inhibitor complex (Ki). All of the tested compounds reversibly inhibited cholinesterases and the Ki constants ranged from 0.02 mM to 6.8 mM, which is typical for low-potency inhibitors. Generally, the affinity (1/Ki) of AChE toward the tested compounds was lower than the affinity of the tested BChE variants. Moreover, the highest selectivity of binding was revealed in the case of albuterol, where the affinity of usual BChE was about 75 times higher compared to AChE. Usual BChE and AChE showed the lowest affinity for adrenaline. Usual BChE showed the highest affinity for fenoterol and the lowest for adrenaline. An analysis of systematic structural differences between compounds revealed that the inhibition potency of the studied compounds could not be related to the disposition of two hydroxyl groups on the benzene ring, but to the size of N-substituents on the aliphatic part of a compound. Our results suggested that, when using beta2-agonists as bronchodilators, one should always keep in mind that they also possess a week inhibition potency for cholinesterases, which leads to a reduction in the level of hydrolytic activity of these enzymes.

human cholinesterases; inhibition; bronchodilators

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