engleski

Interaction of human cholinesterases with bisdimethylcarbamate derivative of albuterol

The selectivity of cholinesterases and their interaction with various compounds, especially drugs, is the subject of many studies in biochemistry and pharmacology, due to their important roles in an organism and involvement in the metabolism of many drugs. One example is bambuterol, a biscarbamate prodrug of terbutaline whose bioconversion in an organism is due to the activity of butyrylcholinesterase (BChE ; EC 3.1.1.8), and whose high therapeutic index is associated with an extremely selective BChE inhibition compared to acetylcholinesterase (AChE ; EC 3.1.1.7). Albuterol is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma. Biscalb, a newly-synthesized bisdimethylcarbamate of albuterol, is structurally related to bambuterol, and we expected it to have a similar BChE inhibition potency and selectivity, as well as stereoselectivity. Inhibition rate can be affected by the BChE gene polymorphism in the human population. The aim of this study was to investigate the inhibition of human BChE (usual, atypical and fluoride resistant) and AChE with biscalb and its (R) and (S) enantiomers to see if their bioconversion is affected by BChE inhibition the same as with bambuterol. Biscalb proved to be a potent inhibitor of all of the studied cholinesterases with inhibition rate constants within 103M-1min-1range. Biscalb inhibited the fastest usual BChE, while achieving the same effect 40 times slower for atypical BChE. Unfortunately, AChE inhibition was only 10 times slower than that of usual BChE, meaning that this selectivity was very poor compared to the 20, 000 faster inhibition of usual BChE as with bambuterol. The studied BChEs did not show any stereoselectivity, while AChE displayed about an 8 times higher preference to (R)-biscalb. The obtained results show that the inhibition profile of biscalb is quite different than that of bambuterol, and cannot be taken in consideration for further investigation as a promising lead for prodrug development in analogy with bambuterol. This research was supported by the Croatian Science Foundation (Grant No.4307).

biscarbamate; albuterol; saligenin

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