Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting β2-adrenoceptor agonists.

摘要: BACKGROUND AND PURPOSE β2-Adrenoceptor agonists are important bronchodilators used for the treatment of chronic obstructive pulmonary disease and asthma. Clinical data on β2-adrenoceptor show a range onset duration action. We have investigated whether receptor binding kinetics can explain their observed action effect in clinic. EXPERIMENTAL APPROACH [3H]-DHA was to label β2-adrenoceptors expressed CHO-cell membranes (Kd 0.084 nM). Competition kinetic experiments were performed presence unlabelled β2 at 37°C HBSS containing GTP. To determine parameters, three concentrations (10, 3 1 ×Ki) compound employed against fixed concentration (0.6 nM). KEY RESULTS The clinically exhibited association dissociation rates. Kd competition Ki values eight examined strongly correlated, suggesting that method had produced accurate koff kon on-rate highly correlated with equilibrium affinity. CONCLUSIONS IMPLICATIONS Although displayed rate simulations relevant drug suggest do not play an role determining clinic. In addition, it is unlikely exert influence these agonists, as indacaterol (once daily dosing) shorter residency time than salmeterol (twice dosing).