RT Journal Article
SR Electronic
T1 Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 600
OP 609
DO 10.1124/jpet.111.179259
VO 337
IS 3
A1 Paola Casarosa
A1 Ines Kollak
A1 Tobias Kiechle
A1 Angela Ostermann
A1 Andreas Schnapp
A1 Ralf Kiesling
A1 Michael Pieper
A1 Peter Sieger
A1 Florian Gantner
YR 2011
UL http://jpet.aspetjournals.org/content/337/3/600.abstract
AB β2-Adrenoceptor (β2-AR) agonists are powerful bronchodilators and play a pivotal role in the management of pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease. Although these agents first were used many years ago, progress in drug development has resulted in better tolerated, long-acting β2-AR agonists (LABAs), such as formoterol and salmeterol. Although LABAs have been on the market for several years, relatively little is known on the rationale(s) behind their long duration of action. In this study, we focused on olodaterol (previously known as BI1744CL), a novel inhaled LABA, which provides a bronchodilating effect lasting 24 h and is currently in Phase III clinical trials. To understand the rationale behind its long duration of action, different aspects of olodaterol were analyzed (i.e., its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the β2-AR). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [3H]olodaterol/β2-AR complex with a dissociation half-life of 17.8 h due to ternary complex formation. The tight binding of olodaterol to the human β2-AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity after extensive washout. Taken together, binding, kinetic, and functional data support the existence of a stable complex with the β2-AR that, with a dissociation half-life >17 h, might indeed be a rationale for the 24-h duration of action of olodaterol.