engleski

Biscarbamate derivatives of bronchodilators are potent and selective butyrylcholinesterase inhibitors

A very desirable characteristic for an asthma drug is prolonged action, providing a patient with a whole night's sleep. This request is met by bambuterol, a biscarbamate prodrug of terbutaline, whose high therapeutic index of bambuterol is associated with its extremely selective inhibition of butyrylcholinesterase (BChE) compared to acetylcholinesterase (AChE). Metacarb and isocarb, newly synthesised biscarbamates of bronchodilators metaproterenol and isoproterenol, are structurally similar to bambuterol and we expected that they should have similar inhibition potency and selectivity in inhibition of BChE. Metacarb and isocarb proved to be very potent BChE inhibitors with 2.2 and 0.2 •106 dm3mol-1min-1 inhibition rate constants, and very selective BChE inhibitors, as they inhibited AChE 960 to 80 times more slowly than BChE, respectively. To elucidate the inhibition potency of studied biscarbamates and bambuterol, we used molecular modelling to study the transition state of carbamylation reaction. Differences in carbamylation rate by metacarb, isocarb and bambuterol can be explained by additional stabilization typical for each carbamate: metacarb by two hydrogen bonds with residues His438 and Glu197, isocarb by the hydrogen bond with Glu197, and bambuterol by the cation–π interaction between protonated nitrogen and Tyr440, and by the hydrogen bond with Glu197. In conclusion, metacarb and isocarb proved far less selective for BChE than bambuterol, and therefore less likely to be used as prodrugs of bronchodilating agents. Acknowledgments: Supported by Ministry of Science, Eduction and Sports, Republic of Croatia (Grant 022-0222148-2889).

acetylcholinesterase; mutants; selectivity; metaproterenol; isoproterenol; inhibition

DOI: 10.1111/j.1742-4658.2010.08705.x