Inhibition of cholinesterases by albuterol carbamate

Abstract

OdreĎene su konstante brzine inhibicije dviju butirilkolinesteraza (BChE; EC 3.1.1.8) i dviju acetilkolinesteraza (AChE; EC 3.1.1.7) s racemičnim, (R)- i (S)- N,N-dimetilkarbamatom albuterola (4-(2-(tert-butilamino)-1-hidroksietil)-2-(hidroksimetil)fenol. Korištene su ljudska (hBChE) i BChE izolirana iz seruma konja (hoBChE), rekombinantna ljudska AChE (hAChE) i AChE izolirana iz električnog organa jegulje (eeAChE). Karbamat albuterola je progresivno inhibirao sve ispitivane kolinesteraze s konstantama brzine inhibicije reda veličine 103-106 dm3mol-1min-1, pri čemu je najbrţe inhibirao hBChE. Ispitivani karbamat se pokazao selektivnim inhibitorom koji hBChE inhibira 8 puta brţe od hAChE. TakoĎer, karbamat albuterola razlikuje kolinesteraze različitih vrsta, budući da hBChE inhibira 1,7 puta brţe od hoBChE, dok hAChE inhibira 34 puta brţe od eeAChE. Ljudske BChE i AChE su stereoselektivni enzimi koji imaju 13, odnosno 4 puta veći afinitet prema (R)-karbamatu albuterola. Inhibicijski potencijal karbamata albuterola, kao i njegova selektivnost prema hBChE u odnosu na AChE, manja je od do sada ispitivanih karbamata slične strukture.Inhibition rate constants of two butyrylcholinesterases (BChE, EC 3.1.1.8) and two acetylcholinesterases (AChE; EC 3.1.1.7) with racemic, (R)- and (S)- albuterol carbamate (4- (2-(tert-butylamino )-1-hydroxyethyl)-2-(hydroxymethyl)phenyl dimethylcarbamate) were determined. Human (hBChE) and BChE from the horse serum (hoBChE), recombinant human AChE (hAChE) and AChE from the eel (eeAChE) were used. Albuterol carbamate progressively inhibited all cholinesterases with inhibition rate constants ranged from 103-106 dm3mol-1min-1, wherefrom inhibition of hBChE was the fastest. Tested carbamate is a selective BChE inhibitor inhibiting hBChE 8 times faster than hAChE. Also, albuterol carbamate clearly distinguishes cholinesterases of different species, since it inhibits hBChE 1.7 times faster than hoBChE, and hAChE 34 times faster than eeAChE. Human BChE and AChE are stereoselective enzymes having 13 or 4 times higher affinity to (R)-carbamate albuterol. The inhibitory potential of albuterol carbamate, as well as its selectivity toward hBChE relative to AChE, is lower than that of other carbamates with the similar structure