Why are long-acting beta-adrenoceptor agonists long-acting?

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

This article has been cited by other articles:

				E. Naline, A. Trifilieff, R. A. Fairhurst, C. Advenier, and M. Molimard Effect of indacaterol, a novel long-acting {beta}2-agonist, on isolated human bronchi Eur. Respir. J., March 1, 2007; 29(3): 575 - 581. [Abstract] [Full Text] [PDF]

				C. Battram, S. J. Charlton, B. Cuenoud, M. R. Dowling, R. A. Fairhurst, D. Farr, J. R. Fozard, J. R. Leighton-Davies, C. A. Lewis, L. McEvoy, et al. In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled beta2 Adrenoceptor Agonist with a 24-h Duration of Action J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 762 - 770. [Abstract] [Full Text] [PDF]

				L. Deng, N. J. Fairbank, D. J. Cole, J. J. Fredberg, and G. N. Maksym Airway smooth muscle tone modulates mechanically induced cytoskeletal stiffening and remodeling J Appl Physiol, August 1, 2005; 99(2): 634 - 641. [Abstract] [Full Text] [PDF]

				M. Laan, S. Bozinovski, and G. P. Anderson Cigarette Smoke Inhibits Lipopolysaccharide-Induced Production of Inflammatory Cytokines by Suppressing the Activation of Activator Protein-1 in Bronchial Epithelial Cells J. Immunol., September 15, 2004; 173(6): 4164 - 4170. [Abstract] [Full Text] [PDF]

				D Price, D Dutchman, A Mawson, B Bodalia, S Duggan, and P Todd Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose Thorax, September 1, 2002; 57(9): 791 - 798. [Abstract] [Full Text] [PDF]

				J. C. KIPS and R. A. PAUWELS Long-acting Inhaled beta 2-Agonist Therapy in Asthma Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 923 - 932. [Full Text] [PDF]

				M. Johnson and S. Rennard Alternative Mechanisms for Long-Acting {beta}2-Adrenergic Agonists in COPD Chest, July 1, 2001; 120(1): 258 - 270. [Abstract] [Full Text] [PDF]

				G. P. ANDERSON Interactions between Corticosteroids and beta -Adrenergic Agonists in Asthma Disease Induction, Progression, and Exacerbation Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S188 - 196. [Full Text] [PDF]

				M. PALMQVIST, T. IBSEN, A. MELLÉN, and J. LÖTVALL Comparison of the Relative Efficacy of Formoterol and Salmeterol in Asthmatic Patients Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 244 - 249. [Abstract] [Full Text]

				A. Teschemacher and H. Lemoine Kinetic Analysis of Drug-Receptor Interactions of Long-Acting beta 2 Sympathomimetics in Isolated Receptor Membranes: Evidence against Prolonged Effects of Salmeterol and Formoterol on Receptor-Coupled Adenylyl Cyclase J. Pharmacol. Exp. Ther., March 1, 1999; 288(3): 1084 - 1092. [Abstract] [Full Text]

				D. CHEUNG, A. M. J. WEVER, J. A. de GOEIJ, C. S. de GRAAFF, H. STEEN, and P. J. STERK Effects of Theophylline on Tolerance to the Bronchoprotective Actions of Salmeterol in Asthmatics In Vivo Am. J. Respir. Crit. Care Med., September 1, 1998; 158(3): 792 - 796. [Abstract] [Full Text] [PDF]

				R. B. Dowling, M. Johnson, P. J. Cole, and R. Wilson The Effect of Rolipram, a Type IV Phosphodiesterase Inhibitor, on Pseudomonas aeruginosa Infection of Respiratory Mucosa J. Pharmacol. Exp. Ther., September 1, 1997; 282(3): 1565 - 1571. [Abstract] [Full Text]

				S. A. Green, A. P. Spasoff, R. A. Coleman, M. Johnson, and S. B. Liggett Sustained Activation of a G Protein-coupled Receptor via ``Anchored'' Agonist Binding. MOLECULAR LOCALIZATION OF THE SALMETEROL EXOSITE WITHIN THE beta 2-ADRENERGIC RECEPTOR J. Biol. Chem., September 27, 1996; 271(39): 24029 - 24035. [Abstract] [Full Text] [PDF]