Abstract
Inhaled β2 adrenoceptor (β2 AR) agonists are widely used as bronchodilator therapies for asthma and COPD. Different agonists have varying rates of onset of action, e.g. indacaterol and salbutamol are effective bronchodilators within 5 min whereas salmeterol takes 15 min to achieve significant bronchodilation over baseline (Brookman et al., Curr Med Res Opin 23:3113–3122, 2007). This has been attributed to differences in the lipophilicity of the agonists such that hydrophobic ligands take longer to diffuse into tissue and may even access the receptor via the membrane compartment (Anderson et al., Eur Respir J 7:569-578, 1994). While this holds true for salmeterol and salbutamol, the relatively high lipophilicity of indacaterol should result in a slower onset of action. Here we have explored the possibility that the efficacy of these ligands may also contribute to their onset of action. We have characterised efficacy and rate of cyclic adenosine monophosphate (cAMP) accumulation in primary human bronchial smooth muscle cells using a competition assay (AlphaScreen, Perkin Elmer) and in HEK 293-GloSensor™ cells endogenously expressing the β2 AR using a luminescence readout. For all agonists tested, cAMP was generated in a concentration-dependent manner. For both assay formats, the relative efficacies were unchanged, with isoprenaline > formoterol > indacaterol > salbutamol > salmeterol. The rate of cAMP generation varied for each agonist and correlated well with intrinsic efficacy in that the high-efficacy agonists promoted the most rapid rise in cAMP levels. We have demonstrated that the rate of cAMP accumulation is influenced by agonist efficacy and that this, in combination with lipophilicity, may explain why β2 AR agonists demonstrate differences in their onset of action.
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Anderson GP, Linden A, Rabe KF (1994) Why are long-acting β-adrenoceptor agonists long-acting? Eur Respir J 7:569–578
Battram C, Charlton SJ, Cuenoud B, Dowling MR, Fairhurst RA, Farr D, Fozard JR, Leighton-Davies JR, Lewis CA, McEvoy L, Turner RJ, Trifilieff A (2006) 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 β2 adrenoceptor agonist with a 24-h duration of action. J Pharmacol Exp Ther 317:762–770
Baur F, Beattie D, Beer D, Bentley D, Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T, Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C, Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M, Watson S, Wissler E, Wyss D (2010) The identification of indacaterol as an ultra-long-acting inhaled β2-adrenoceptor agonist. J Med Chem 53:3675–3684
Brookman LJ, Knowles LJ, Barbier M, Elharrar B, Fuhr R, Pascoe S (2007) Efficacy and safety of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and salbutamol in patients with asthma. Curr Med Res Opin 23:3113–3122
Cazzola M, Matera MG (2009) Emerging inhaled bronchodilators: an update. Eur Respir J 34:757–769
Dahl R, Greefhorst LAPM, Nowak D, Nonikov V, Byrne AM, Thomson MH et al (2001) Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Resp Crit Care 164:778–784
Deshpande DA, Theriot BS, Penn RB, Walker JKL (2008) β-Arrestins specifically constrain β2-adrenergic receptor signaling and function in airway smooth muscle. FASEB 22:2134–2141
Drake MT, Violin JD, Whalen EJ, Wisler JW, Shenoy SK, Lefkowitz RJ (2008) β-arrestin-biased agonism at the β2-adrenergic receptor. J Biol Chem 283:5669–5676
Friedman J, Babu B, Clark RB (2002) β2-adrenergic receptor lacking the cyclic AMP-dependent protein kinase consensus sites fully activates extracellular signal-regulated kinase 1/2 in human embryonic kidney 293 cells: lack of evidence for Gs/Gi switching. Mol Pharmacol 62:1094–1102
Kikkawa H, Naito K, Ikezawa K (1991) Tracheal relaxing effects and β2-selectivity of Ta-2005, a newly developed bronchodilating agent, in isolated guinea-pig tissues. Jpn J Pharmacol 57:175–185
Krasel C, Vilardaga JP, Bunemann M, Lohse MJ (2004) Kinetics of G-protein-coupled receptor signalling and desensitization. Biochem Soc Tran 32:1029–1031
Lombardi D, Cuenoud B, Kramer SD (2009) Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties? Eur J Pharm Sci 38:533–547
Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M (2007) Effect of indacaterol, a novel long-acting β2-agonist, on isolated human bronchi. Eur Respir J 29:575–581
Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, Lotvall J (1997) Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 10:2484–2489
Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Butchers PR, Coe DM, Conroy R, Edney DD, Field RN, Ford AJ, Guntrip SB, Looker BE, McLay IM, Monteith MJ, Morrison VS, Mutch PJ, Richards SA, Sasse R, Smith CE (2009) Synthesis and structure-activity relationships of long-acting β2 adrenergic receptor agonists incorporating arylsulfonamide groups. J Med Chem 52:2280–2288
Rennard S, Bantje T, Centanni S, Chanez P, Chuchalin A, D’Urzo A, Kornmann O, Perry S, Jack D, Owen R, Higgins M (2008) A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison. Respir Med 102:1033–1044
Rhodes DG, Newton R, Butler R, Herbette L (1992) Equilibrium and kinetic studies of the interactions of salmeterol with membrane bilayers. Mol Pharmacol 4:596–602
Rosethorne E, Charlton SJ (2008) Rate of β-arrestin recruitment to the β2 adrenoceptor is governed by agonist efficacy. pA2online 6(1):002P
Sears MR, Lotvall J (2005) Past, present and future–β2-adrenoceptor agonists in asthma management. Respir Med 99:152–170
Sharma RK, Jeffery PK (1990) Airway beta-adrenoceptor number in cystic fibrosis and asthma. Clin Sci (Lond) 78:409–417
Sturton RG, Trifilieff A, Nicholson AG, Barnes PJ (2008) Pharmacological characterization of indacaterol, a novel once daily inhaled β2 adrenoceptor agonist, on small airways in human and rat precision-cut lung slices. J Pharmacol Exp Ther 324:270–275
Traynor JR, Clark MJ, Remmers AE (2002) Relationship between rate and extent of G protein activation: comparison between full and partial opioid agonists. J Pharmacol Exp Ther 300:157–161
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Rosethorne, E.M., Turner, R.J., Fairhurst, R.A. et al. Efficacy is a contributing factor to the clinical onset of bronchodilation of inhaled β2-adrenoceptor agonists. Naunyn-Schmied Arch Pharmacol 382, 255–263 (2010). https://doi.org/10.1007/s00210-010-0533-6
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DOI: https://doi.org/10.1007/s00210-010-0533-6